Visceral fat and metabolic syndrome -
Gluteofemoral adipose mass is positively associated with insulin sensitivity in humans, coupled with a slower rate of lipolysis and subsequent FFA release, lower levels of inflammatory cells and cytokines, and elevated adipokines such as leptin and adiponectin Evidence from animal models has suggested that transplantation of subcutaneous WAT into the visceral cavity of recipient mice promotes less body weight and adiposity gain than transplantation with visceral WAT, resulting in greater insulin sensitivity in the liver and endogenous WAT Taken together, a growing body of evidence suggests that adipose tissue and ectopic lipid distribution contribute to whole-body glucose homeostasis.
With the purported potential to improve glucose homeostasis, interest in BAT and beige adipose tissue as therapeutic targets has increased in recent years.
Studies in rodents in which BAT is transplanted into diseased mouse models have shown that transplanted BAT improves insulin sensitivity, glucose metabolism, and obesity — , likely mediated by batokine effects.
As a highly metabolically active organ, BAT contributes to glucose clearance by taking up relatively large amounts of glucose from the circulation, thus reducing insulin secretion by pancreatic β-cells Indeed, individuals that possess detectable BAT have lower fasting glucose concentrations than those without active BAT Glucose disposal through activated BAT occurs by both insulin-dependent and insulin-independent mechanisms For example, the cold exposure-mediated influx of glucose into active BAT has been suggested to be an insulin-independent process — However, as the insulin receptor is highly expressed in BAT tissue, it is considered to be one of the most sensitive insulin target tissues and thus an important organ for glucose disposal BAT activation further enhances insulin signaling in BAT itself by augmenting insulin-independent glucose uptake associated with thermogenesis and glucose uptake due to insulin signaling.
Thus, strategies that activate BAT and beige adipose tissue have the capacity to improve insulin resistance by clearing excess glucose — Several pathologic conditions, including hypercholesterolemia and systemic inflammation, are hypothesized to drive atherosclerotic CVD.
With a primary function of sequestering lipotoxic lipids and the known potential for chronic inflammation, obese adipose tissue has emerged as a potential player in the regulation of these atherogenic factors.
Obesity has been officially classified as an independent risk factor for CVD by the American Heart Association since , meaning that obesity treatment is likely to lower the incidence of CVD As alluded to in previous sections, people with MHO are at a lower risk of experiencing cardiovascular events than people with MUHO , yet those without obesity are at a considerably lower risk for future events.
Thus, even a moderate level of weight loss, if sustainable, could potentially lower the risk of adverse CVD events Possible reasons include confounding factors such as smoking and the presence of co-morbidities that are associated with lower body weights, or the use of BMI rather than measures of visceral obesity for most studies on the obesity paradox.
Despite the obesity paradox in those with established CVD, the following sections will provide information regarding potential links between obesity T2DM and CVD. The various features of adipose tissue depots, including ectopic fat, and how they contribute to T2DM and CVD are summarized in Figure 2.
Notably, there are many similarities between adipose depot characteristics that contribute to both T2DM and CVD. Figure 2. Adipose depots and ectopic fat sites and their features that contribute to type 2 diabetes mellitus T2DM or cardiovascular disease CVD.
Features of intra-abdominal white adipose tissue WAT , subcutaneous fat, hepatic fat, heart and arterial fat inclusive of epicardial, pericardial, and perivascular fat , pancreatic fat, skeletal muscle fat, brown adipose tissue, and a dysbiotic gut that contribute to either T2DM or CVD.
Arrows indicate changes in comparison with subjects without T2DM or CVD. The accumulation of visceral fat in obesity is associated with the metabolic syndrome, its associated CVD risk factors, and an increased risk for clinical CVD This distribution of WAT has been shown to have the greatest effect on CVD risk and mortality among patients with normal body weight The risk of CVD in the metabolic syndrome has been considered to result from the presence of multiple CVD risk factors such as dyslipidemia hypertriglyceridemia, an excess of small, dense LDL particles and reduced HDL-cholesterol levels , hypertension, dysglycemia, and a thrombogenic profile that have been reviewed elsewhere — However, there are several additional potential mechanisms by which visceral WAT might contribute directly to CVD that involve FFA, insulin resistance, and inflammation.
Visceral WAT has higher lipolytic activity than subcutaneous WAT due to its having fewer insulin receptors, and thus is a significant source of FFA.
Visceral-derived FFA can directly impact the liver via the portal vein, facilitating FFA uptake by the liver and subsequent hepatic insulin resistance. Similarly, excess FFA from visceral fat might directly impair lipid metabolism and lead to dyslipidemia, which increases CVD risk.
In obese diabetic subjects, plasma FFA levels have been shown to be elevated compared to BMI-matched non-diabetic subjects , supporting the notion that insulin resistance further elevates circulating FFA levels. Moreover, the incidence of T2DM is nearly doubled in patients with the highest levels of FFA 90th percentile when compared with subjects with the lowest FFA levels 10th percentile In one study, obese T2DM subjects who had undergone overnight fasting during pharmacological inhibition of lipolysis exhibited improved insulin sensitivity and glucose tolerance , providing further evidence for an inhibitory effect of FFA on insulin sensitivity.
The adipokine profile of visceral WAT also contributes substantially to its association with CVD risk. Obese visceral WAT primarily secretes inflammatory cytokines such as resistin, TNFα, IL-6, IL-1β, MCP-1, and SAA, with reduced levels of adiponectin Plasma adiponectin levels are decreased in patients with CVD Adiponectin is believed to contribute to CVD protection by several mechanisms, including the reduction of lipid levels, repressing expression of inflammatory mediators such as VCAM, ICAM, E-selectin, TNFα, and IL-6, and by acting directly on the heart to improve ischemic injury by activating AMPK and subsequently increasing energy supply to the heart — Adiponectin also stimulates endothelial nitric oxide synthase eNOS , which maintains healthy vascular tone , Thereby, adiponectin would play a protective role in the development of CVD.
Conversely, leptin levels are positively associated with acute myocardial infarction, stroke, coronary heart disease, chronic heart failure, and left cardiac hypertrophy — , although the reasons for this remain largely unknown. Leptin receptors are expressed in the heart, indicative of an important impact of direct leptin signaling Resistin is positively associated with systemic inflammatory markers , upregulates endothelial expression levels of VCAM-1 and endothelin-1 and promotes the proliferation of smooth muscle cells Resistin also associates positively with coronary artery calcification levels, and negatively with HDL cholesterol Thus, adipose-derived resistin levels could be used to predict the severity of coronary atherosclerosis Similarly, cytokines and chemokines such as those secreted from obese visceral WAT can induce expression of endothelial adhesion molecules , recruit macrophages , increase thrombosis , and reduce vasoreactivity , and are positively associated with cardiovascular events , While visceral WAT-derived cytokines are associated with these CVD-inducing processes, it is important to note that the direct contribution from visceral WAT is not currently known, as these are also secreted from other tissues.
As discussed in previous sections, in addition to cytokines and exclusive adipokines, WAT is also a source of FGF While the liver is considered to be the major source, adipocytes have also been shown to produce FGF21 to varying degrees in response to various stimuli.
In addition to its associations with obesity and T2DM, FGF21 levels have also been associated with increased risk for CVD — Subjects with CVD that also had diabetes exhibited even higher levels of FGF21 , suggesting an important role in diabetes-accelerated atherosclerosis.
In particular, FGF21 levels have been shown to positively correlate with hypertension and triglyceride levels, and to negatively correlate with HDL-cholesterol levels One study by Lee et al. suggested that plasma FGF21 levels are associated pericardial fat accumulation , which suggests that ectopic fat could be a source of FGF21 in metabolic disease.
Further studies are needed to discern whether adipocyte- or hepatic-derived FGF21 contribute to these effects. In stark contrast to these effects of physiological FGF21, pharmacological administration of FGF21 in humans and non-human primates reduces blood glucose, insulin, triglycerides, and LDL cholesterol, and increases HDL cholesterol , , Thus, there is a disconnect between the physiological and pharmacological effects of FGF21 that requires further study.
It is becoming increasingly clear that adipose tissue expansion contributes directly to obesity-associated cardiovascular disease risk Obesity is accompanied by not only excess visceral adiposity, but also by excess epicardial and perivascular WAT Due to their proximity to the heart, coronary arteries, and other major arterial blood vessels that are prone to atherosclerosis, it is not surprising that epiWAT and PVAT are important regulators of cardiac and vascular.
The respective sizes of these adipose depots are associated with risk factors for the metabolic syndrome, including elevated visceral fat content, blood glucose, hypertension, systemic inflammation, insulin resistance, circulating LDL levels, mean arterial pressure, and atherosclerosis 19 , — , as well as adverse cardiovascular events — The mechanisms behind these associations include increased secretion of pro-inflammatory cytokines, vasoactive factors, and vascular growth factors — ; increased release of lipotoxic FFA , ; increased macrophage content ; increased oxidative stress ; and decreased secretion of adiponectin , which are triggered by obesity.
In a prospective cohort of patients with aortic stenosis, a positive association between epiWAT volume and left ventricular mass was found , suggesting that in addition to changes in adipokine secretion, epiWAT could negatively influence cardiac function by placing a restrictive burden on the heart.
Mechanisms by which PVAT influences CVD are more nuanced and complex. As an adipose depot that features some characteristics of both WAT and BAT, and with different functions depending on the anatomical location i.
abdominal aortic PVAT , PVAT can play either a cardioprotective or a pathological role As obesity progresses, PVAT can become dysfunctional in that it more resembles WAT, and contributes to a pro-inflammatory and lipotoxic microenvironment that promotes atherosclerosis Thus, while PVAT and BAT play atheroprotective roles in healthy individuals, obesity promotes dysfunction of these depots, blunting this protective effect against CVD.
Strategies for weight loss are multi-faceted, including combinations of diet and lifestyle modifications, pharmaceutical therapy, and various forms of bariatric surgery While there is some debate over this, it is generally believed that small degrees of weight loss in MUHO obese populations can have a dramatic impact on cardiometabolic health , ; thus, strategies that improve obesity are likely to also decrease risk factors for CVD.
Similarly, CVD treatment strategies are centered around a combination of pharmaceutical use and lifestyle modifications, which also impact adipose tissue.
In this section, we will describe the effects that various CVD treatment strategies have on adipose tissue metabolism and inflammation. How these treatment strategies impact the contributions of particular adipose depot features to T2DM and CVD are listed in Figure 2.
Traditional methods prescribed for weight loss include restricting food intake and increasing energy expenditure. Despite a large number of fad diets that dictate particular proportions of dietary fat, protein, and carbohydrates to facilitate weight loss [summarized in , ], the simple fact remains that for weight loss to occur, energy balance must be negative.
Thus, energy intake must be less than energy expended, which includes resting energy expenditure, physical activity, and the thermic effect of food. Subsequently, additional studies have shown that modest weight loss due to dietary changes in people with overweight or obesity is due to roughly equivalent fat lost from subcutaneous and visceral depots, while the addition of exercise leads to more weight loss from subcutaneous fat as well as loss of ectopic skeletal muscle fat — The loss of visceral fat is associated with reduced CVD risk factors, including reduced systemic inflammation, total cholesterol, LDL cholesterol, and triglycerides , , as well as reduced fasting glucose and insulin levels , As the subjects recruited for the Look AHEAD trial had T2DM, this and other post-hoc analyses suggest that weight loss in T2DM subjects also lowers the risk of CVD events , It is well established that aerobic exercise increases fuel mobilization from adipose tissue by increasing lipolysis and subsequent FFA mobilization, which ultimately decreases adiposity and adipocyte size — Such enhanced fuel mobilization is thought to be highest for visceral WAT Hepatic fat is also mobilized and decreased following intense aerobic exercise Studies in mice suggest that not only visceral fat mass is lost with regular exercise, but subcutaneous and brown fat mass are also diminished As expected with fat loss, exercise is coincident with reduced plasma and adipose tissue leptin levels — The effects of exercise-induced fat loss on adiponectin levels are less clear, with some studies showing no changes in circulating adiponectin levels — , some showing increased plasma adiponectin — , and others showing increased subcutaneous WAT expression of adiponectin mRNA — A meta-analysis showed that pediatric subjects with obesity exhibit reduced resistin levels following aerobic exercise Little is known about the impact of exercise on FGF21 in obese humans, but one study suggested that aerobic exercise training in obese women reduced circulating FGF21 levels By contrast, studies in rodents have shown that circulating FGF21 levels are not altered by exercise in obese animals Collectively, such exercise-induced changes to WAT distribution and adipokine secretion likely facilitate the observed improvements in insulin sensitivity and CVD risk factors observed with exercise.
While many studies have reported that exercise training increases subcutaneous WAT browning in rodent models of obesity — , there is limited data to support this in humans.
Many studies have shown that there is no effect of aerobic exercise training to recruit beige adipocytes in humans However, one study compared subcutaneous WAT from lean, sedentary young men with age- and weight-matched endurance-trained men and reported no differences in beige markers such as UCP1, PGC1A , or CIDEA Another study found evidence of subcutaneous WAT browning i.
There is some debate about what role brown or beige adipose tissue would play in exercise, if it indeed occurs. Exercise is known to activate the sympathetic nervous system, which also activates BAT to quickly release stored energy, so it is possible that BAT activation is secondary to exercise-induced sympathetic activation Loss of adipose tissue mediated by dietary changes, exercise, liposuction, or bariatric surgery discussed in the section on Bariatric Surgery is accompanied by decreased markers of adipose tissue and systemic inflammation , Fat loss by liposuction yielded similar changes in systemic inflammatory markers in one study , but did not improve plasma cytokine levels in another The removal of visceral fat from Zucker diabetic fatty rats resulted in dramatic reductions in systemic cytokines ; this suggests that removing visceral fat, rather than the subcutaneous fat that is routinely removed during liposuction, is more advantageous in terms of resolving inflammation.
Many studies also have shown that weight loss following bariatric surgery leads to reductions in systemic inflammatory markers , with notable reductions in adipose tissue inflammatory cytokine and macrophage expression — However, some similar studies do not show improvements in adipose tissue inflammation following various weight loss modalities, such as bariatric surgery or very low-calorie diets — It has been suggested that pronounced weight loss over time can lead to improvements in adipose tissue inflammation that were not observed in the same subjects following acute moderate weight loss This implies that adipose tissue inflammation during the initial stages of weight loss could be required for the pronounced adipose tissue remodeling required for fat loss , Metformin is the most commonly prescribed medication to treat T2DM, particularly in subjects with obesity Metformin has been proposed to lower blood glucose levels through suppression of gluconeogenesis in the liver, activation of AMP-activated protein kinase AMPK , inhibition of the mitochondrial respiratory chain complex 1 , and by unknown mechanisms in the gut , Thus, the precise mechanisms by which metformin lower blood glucose are complex and still evolving.
While some diabetes medications have adverse effects on body weight, patients taking metformin often lose a small amount of weight [reviewed in ]. Studies in T2DM suggest that metformin may reduce body fat stores and promote a more metabolically healthy fat distribution — The effect of metformin on adiposity may be partially due to reported nausea and anorexic effects of the drug — With much recent attention focused on BAT as a potential target for obesity treatment, it has recently been shown that BAT is an important effector organ in the glucose-lowering effects of metformin Some studies have reported increases in omentin following metformin therapy, which could be due to visceral fat loss Metformin also reduces hepatic steatosis through inhibition of ApoA5 and steroyl-CoA desaturase-1 SCD1 which combine to limit de novo lipid synthesis, which is partially mediated by its actions on AMPK and liver X receptor LXR activity , It also has been suggested that metformin reduces ECM remodeling that is dysregulated in obesity see previous section on adipose tissue plasticity , and reduces lipogenesis In addition to the increasingly recognized anti-obesity effects of metformin, its ability to improve CVD risk is also becoming apparent The mechanism may include improvements in the lipid profile, such as mild reductions in plasma VLDL cholesterol and triglycerides with slight elevations in HDL cholesterol In addition, metformin has been shown to have anti-inflammatory properties, reported to reduce circulating CRP and MCP-1, reduce NFκB activity, and to reduce advanced glycation end products AGE — Glucagon-like peptide-1 GLP-1 is a peptide hormone that is continuously secreted at low levels during fasting by intestinal L cells.
Consumption of a meal enhances GLP-1 secretion, which functions to reduce plasma glucose levels by stimulating insulin secretion from pancreatic beta cells. In addition, GLP-1 receptors are abundant in brain areas that control food intake regulation, such as the hypothalamus, where GLP-1 functions to reduce the drive to eat , Thus, several GLP-1 receptor agonists have been developed to mimic the glucose-lowering and anorexic effects of GLP-1 to treat obesity and T2DM.
Liraglutide, a GLP-1 receptor agonist, has shown efficacy in not only glucose control, but also in promoting weight loss and reduced waist circumference based on results from the Liraglutide Effect and Action in Diabetes LEAD study — Liraglutide has also been shown to reduce total adiposity, and specifically visceral fat mass , While initially described as being devoid of GLP-1 receptors , it has now been confirmed that adipocytes express the GLP-1 receptor , Adipose tissue may therefore be an additional target for GLP-1 receptor agonists to promote adipose remodeling by unknown mechanisms.
In addition to its effects on body weight and glucose metabolism, GLP-1 receptor agonists may also provide protection against CVD The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results LEADER trial showed that liraglutide lowered the risk of myocardial infarction and non-fatal stroke among patients with T2DM that had high CVD risk GLP-1 receptor agonist treatment has been shown to protect against atherosclerosis in animal models and in humans, potentially by lowering plasma lipids and by reducing circulating CRP and soluble ICAM-1 levels — Liraglutide, when administered in combination with metformin as indicated for the treatment of T2DM, has been shown to reduce epicardial WAT volume with simultaneous increased omentin expression Thus, liraglutide may provide cardioprotection through reduced levels of ectopic fat, lipids, and inflammation.
Inhibitors of the sodium-glucose cotransporter 2 SGLT-2 have been shown to reduce blood glucose levels in subjects with T2DM by enhancing urinary glucose excretion The SGLT-2 inhibitor empagliflozin, alone and in combination with the GLP-1 receptor agonist liraglutide, has been shown to reduce CVD risk , as well as cardiovascular death to a greater extent than statins alone Empagliflozin also is associated with decreased hypertension, reduced arterial stiffness, and decreased vascular resistance , In both rodents and humans with non-alcoholic fatty liver disease, SGLT-2 inhibitors have been shown to reduce ectopic liver fat by blunting de novo hepatic lipogenesis — , with reduced alanine transaminase ALT and aspartate transaminase AST levels , two markers of hepatic metabolic stress.
Furthermore, empagliflozin is associated with weight loss in humans when administered in combination with other therapeutics, such as metformin, thiazolidinediones, and sulfonylureas — In rodents, SGLT-2 inhibitors have been shown to suppress high fat diet-induced weight gain and to markedly reduce obesity-induced inflammation in WAT, potentially by increasing fat oxidation and the recruitment of beige adipose tissue , Thus, in addition to correcting hyperglycemia, SGLT-2 inhibitors can also impact adipose tissue physiology; whether this is through direct or indirect mechanisms remains to be elucidated.
Bariatric surgical techniques, including Roux-en-Y gastric bypass RYGB and sleeve gastrectomy, are widely acknowledged to be the most effective treatment strategies for obesity, achieving relatively low levels of obesity remission Within the first year of surgery, some patients experience the loss of around half of their adipose tissue mass , often with roughly equivalent losses from subcutaneous and visceral WAT , As weight loss progresses, studies have shown that later weight loss is largely from visceral depots — , an effect that correlates with the degree of diabetes remission It has also been reported that ectopic skeletal muscle and pancreatic fat are reduced following bariatric surgery , , , which could contribute to improved glucose metabolism.
Studies in humans have reported that subcutaneous adipocytes become smaller following bariatric surgery, resembling adipocytes from lean individuals, but that total adipocyte number remains unchanged , Little is known regarding the size and number of visceral adipocytes, which are extremely difficult to sample from humans.
As expected with reduced adipocyte size, leptin levels have been shown to decrease following bariatric surgery, while adiponectin has been shown to increase in some studies , , but not in others , Whether changes in adipokine secretion are important for the sustained metabolic improvements following bariatric surgery or whether they simply reflect the adipose remodeling remain to be elucidated.
However, it is worth noting that one study has shown that adiponectin levels are elevated only 2 weeks following bariatric surgery, before significant weight loss has occurred, suggesting that adipokine responses may be independent from weight loss Following bariatric surgery, obesity-associated systemic inflammation persists for as much as 1 month, as indicated by IL-6 and CRP levels , , Some of this inflammation has been attributed to the surgery itself However, by 6 to 12 months post-surgery, circulating IL-6, CRP, and MCP-1 are typically reduced below pre-surgery levels , , — , an effect that may be due to fat loss.
Importantly, it is not yet clear what effect weight loss due to bariatric surgery has specifically on adipose tissue inflammation. With insulin sensitivity being substantially improved in all of these studies, these latter studies present a potential disconnect between adipose tissue inflammation and insulin sensitivity that requires further study.
However, it must be noted that the adipose tissue sampled in these studies was from subcutaneous depots, due to ease of sampling. Given that visceral WAT is more prone to inflammatory changes, it is possible that visceral WAT inflammation is more impacted by bariatric surgery than subcutaneous WAT.
Bariatric surgery has been shown to upregulate FGF21 in humans, an effect that appears to be specific to RYGB-induced weight loss, as this effect is not observed following weight loss due to caloric restriction or sleeve gastrectomy — Importantly, it is not known if such FGF21 derives from the liver or adipose tissue.
One study has shown that increased FGF21 is associated with improved HOMA-IR in RYGB subjects, an effect that remains when adjusted for adiposity , introducing the possibility that elevated FGF21 levels serve to impact glucose homeostasis. Given that FGF21 has been shown to be elevated in obesity, and in particular in subjects with insulin resistance , the notion that FGF21 levels would become even further elevated following RYGB surgery, a procedure which rapidly improves insulin sensitivity, represents a paradox.
Various forms of bariatric surgery have been shown to evoke long-term benefits including sustained and considerable weight loss as well as rapid and sustained remission of T2DM and reduced risk of CVD-related mortality Bariatric surgery also is associated with improved hypertension, but not a reduced risk of incident hypertension Interestingly, the CRP reduction observed following bariatric surgery was most pronounced in subjects that regained the most insulin sensitivity , suggesting an important link between improved glucose metabolism and CVD.
TZDs are synthetic peroxisome proliferator-activated receptor gamma PPARγ activators that have been used to treat T2DM for decades — The mechanism for such improvements in insulin sensitivity in the face of weight gain appears to be through the induction of adiponectin by TZDs , which has known insulin-sensitizing properties as described above.
Activation of PPARγ by TZDs not only enhances adipogenesis, it also alleviates inflammatory cytokine secretion associated with obesity and reduces ectopic fat deposition in tissues such as the liver and skeletal muscle There appears to be a reciprocal relationship between inflammatory cytokines and adiponectin.
For example, in vitro experiments in cultured adipocytes revealed that treatment with adiponectin reduces cytokine secretion , , while treatment with cytokines drastically reduces adiponectin expression and secretion , , Due to greater adipose lipid storage potential, TZDs should therefore reduce plasma triglyceride levels, which appears to be the case for pioglitazone but not rosiglitazone — This may in part account for the beneficial cardiovascular effects of pioglitazone in a clinical trial Characteristic features of MUHO and the metabolic syndrome include adipose tissue and systemic inflammation, which may play a role in the pathogenesis of atherosclerotic CVD.
Therefore, an approach that inhibits inflammation would seem logical. The CANTOS trial, in which CVD events were reduced using an IL-1β antagonist, canakinumab , was the first successful proof of concept study using an anti-inflammatory approach for the prevention of recurrent CVD events.
A more recent study showed that colchicine, an old drug that has powerful anti-inflammatory properties, reduced recurrent ischemic events when administered after a myocardial infarction Statins, which inhibit 3-hydroxymethyl-glutaryl-coenzyme A reductase HMG-CoA reductase to reduce LDL cholesterol levels, also have anti-inflammatory properties — Whether this anti-inflammatory effect of statins plays a role in the well-documented effect of statins in inhibiting clinical CVD events and CVD mortality , is unknown.
Even less is known about the effect of statins on inhibiting inflammation in adipose tissue, although statins have been shown to reduce epicardial fat accumulation A clue to the potential role of statins in adipose tissue inflammation is provided by the recent demonstration that myeloid-specific deletion of HMG-CoA reductase improved glucose tolerance in obesity induced by a high fat diet, as a result of decreased macrophage recruitment into adipose tissue These changes occurred independently of weight loss and provide impetus for further studies on the effect of statins on adipose tissue inflammation.
Regardless, the effect of statins on adipose tissue inflammation is an area that warrants further investigation. The trillions of bacteria that reside within our digestive tract, termed gut microbiota, play an important symbiotic role in shaping our metabolic health.
The specific bacterial populations that inhabit our gut can have substantial metabolic impact in relation to obesity, as it is becoming increasingly recognized that that the gut microbiota may contribute to the pathology of obesity — Dysbiosis, or microbial imbalance in the body, has been associated with obesity in both humans and mice, and can be reversed with weight loss — It is known that gut bacteria can influence distinct host organ systems indirectly and specifically through the release of particular microbial metabolites such as bile acids, short-chain fatty acids SCFA , and others.
Adipose tissue is a notable target of these microbial metabolites As such, treatments that target the microbiome and modulate microbial metabolism could improve metabolic health.
There is growing evidence that gut dysbiosis can contribute directly to atherosclerotic CVD — , These processes are described below. Increased intestinal permeability allows inflammatory bacterial components to enter the systemic circulation to trigger an inflammatory response in diverse tissues such as the liver and adipose tissue.
Obese mice and humans have been shown to exhibit gut dysbiosis , with increased proportions of endotoxin-producing gut bacteria and elevated circulating levels of lipopolysacharide that correlate with metabolic disease state such as obesity or T2DM , Such metabolic endotoxemia is reduced following antibiotic treatment or RYGB surgery-induced weight loss Thus, a compromised intestinal barrier may contribute to systemic inflammation that is characteristic of obesity and CVD Gut dysbiosis contributes to dysregulated bile acid metabolism , leading to hyperlipidemia and hyperglycemia , Bile acids produced by the liver facilitate the absorption of dietary fat in the small intestine, and are known to regulate lipid and glucose metabolism through the FXR , FXR activation by bile acids initiates a negative feedback pathway, such that bile acid synthesis is inhibited when FXR is activated.
Secondary bile acids have been shown to exert an anti-inflammatory phenotype in macrophages and hepatocytes — Bariatric surgery increases plasma bile acid concentrations before any significant weight loss has been achieved — Metabolic benefits from bariatric surgery, including weight loss and improved glucose metabolism, were absent in mice lacking the TGR5 receptor , suggesting an important role for bile acids in the metabolic improvements associated with bariatric surgery.
Indeed, adipocyte TGR5 is required for adipogenesis and a metabolically healthy adipokine profile, including secretion of adiponectin and repression of inflammatory cytokines , Similarly, deficiency of FXR promotes adipocyte dysfunction, exemplified by impaired adipogenesis, defective insulin signaling, and reduced lipid storage capacity Collectively, these previous studies suggest that intact bile acid signaling is required for adipocyte homeostasis.
Thus, equilibrium between dietary-intestinal- and microbiome-intestinal-derived bile acids is important for metabolic health associated with lipid metabolism. The gut microbiota composition and metabolism are therefore important contributors to metabolic health.
SCFA, including predominantly acetate, propionate, and butyrate, are produced in the gut to varying degrees, depending on the fermentable carbohydrate-based substrates available i.
SCFA serve as signaling molecules to remote organ systems, with impacts on autonomic regulation of systemic blood pressure, systemic inflammation, and other cellular functions.
Dysbiotic gut bacteria that is observed in metabolic pathologies such as obesity and T2DM has been characterized by taxonomic shifts that produce fewer SCFA, with notably less butrate produced in the gut — Evidence from pre-clinical models suggests that SCFA administration could improve metabolic disease states such as obesity, T2DM, and atherosclerosis — Adipocytes express high levels of key receptors for SCFA, including GPR43 Genetic deletion of GPR43 from adipocytes results in spontaneous obesity, while overexpression of adipocyte GPR43 protects mice from obesity As such, adipose homeostasis can be directly modulated by the gut microbial composition and subsequent SCFA profile.
Health benefits of giving SCFA to obese rodents include weight loss , improved glucose metabolism, reduced inflammation — , and reduced LDL-cholesterol , , among others.
The gut microbiota are now considered to be a distinct organ system with endocrine properties that can directly and profoundly modulate the host immune system , When gut bacteria become dysbiotic, resulting immune deficiencies may contribute to the pathogenesis of obesity, T2DM, and CVD The precise mechanisms by which gut microbiota modulate host immunity [reviewed in ] are beyond the scope of this review.
However, some mechanisms by which microbial-derived metabolites can modulate adipose tissue function will be described herein. SCFA such as butyrate have been shown to dampen subcutaneous and visceral WAT inflammation by inhibiting NFκB activation , Diabetes 53 , —, doi: Cornier, M.
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Gut 57 , —, doi: Grundy, S. Diagnosis and Management of the Metabolic Syndrome. The Asia-Pacific perspective: redefining obesity and its treatment Download references. This work was supported by a grant from the SNUH Research Fund Number The funding organizations had no role in the design or conduct of the study; in the collection, management, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript.
Department of Family Medicine, Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea.
Department of Internal Medicine, Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea. Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, United States. You can also search for this author in PubMed Google Scholar.
Study concept and design: D. and H. Acquisition of data: H. and D. Analysis and interpretation of data: D. and J. K Drafting of the manuscript: H. Critical revision of the manuscript for important intellectual content: D. Statistical analysis: D. Obtaining funding: H.
Study supervision: D. Correspondence to Donghee Kim. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open Access This article is licensed under a Creative Commons Attribution 4. Reprints and permissions. Kwon, H. Body Fat Distribution and the Risk of Incident Metabolic Syndrome: A Longitudinal Cohort Study.
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Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. nature scientific reports articles article. Download PDF. Subjects Metabolic syndrome Obesity. Abstract The effect of visceral adipose tissue VAT and subcutaneous adipose tissue SAT area on metabolic syndrome MS has been debated.
Results General characteristics of the study population As outlined in the Methods section, of the 5, subjects in the baseline cohort, 2, Full size table. Table 4 Incidence of each component of MS by the VAT and SAT areas at baseline.
Discussion In this large prospective study, the VAT area was longitudinally associated with incident MS and its components during a 5-year follow-up period. Methods Study subjects and design This longitudinal study was performed using a previously described cohort 8.
Anthropometric and laboratory measurements The methods applied in this cohort have been described in detail elsewhere 8 , 35 , Measurement of abdominal adipose tissue Detailed descriptions of the methods used to measure the abdominal adipose tissue area have been published previously Statistical analysis The outcome of this study was the development of MS.
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They tend to be lower in the lean and normal weight subjects than in the obese As indicated by Bouchard et al. When they examined the relationship of total body fat mass to visceral adipose tissue accumulation in men and in premenopausal women, Lemieux et al. Furthermore, the relationship of visceral adipose tissue to metabolic complications was found to be independent of concomitant variation in total body fat, and it was concluded that the assessment of cardiovascular risk in obese patients solely from the measurement of body weight or of total body fatness may be completely misleading 19 , 22 , 36 , Indeed, it appears that only the subgroup of obese individuals characterized by a high accumulation of visceral adipose fat show the complications predictive of type 2 diabetes and cardiovascular disease On the other hand, after adjustment for total body fat, Abate et al.
Intraabdominal visceral fat is associated with an increase in energy intake but this is not an absolute requirement. Positive energy balance is a strong determinant of truncal-abdominal fat as shown by Bouchard and colleagues 96 in overfeeding experiments in identical twins.
The correlations between gains in body weight or total fat mass with those in subcutaneous fat on the trunk reached about 0. In contrast, these correlations attained only 0. Thus, positive energy balance does not appear to be a strong determinant of abdominal visceral fat as is the case with other body fat phenotypes 7.
In effect, as discussed in the CT section of imaging techniques for evaluation of intraabdominal visceral fat, some investigators 70 , 71 have shown that either when the subjects lose or increase their weight, particularly females, visceral fat is lost or gained, respectively, less than subcutaneous fat at the abdominal level.
However, at variance from these data, Zamboni et al. Similarly, as already mentioned, Smith and Zachwieja 32 noted that all forms of weight loss affect visceral fat more than subcutaneous fat percentage wise , and there was a gender difference, with men appearing to lose more visceral fat than women for any given weight loss.
LPL activity, being related to the liberation of the lipolytic products [from chylomicra and very-low-density lipoproteins VLDL ] to the adipocytes for deposit as triglycerides, is a key regulator of fat accumulation in various adipose areas, since human adipose tissue derives most of its lipid for storage from circulating triglycerides.
However, adipocytes can synthesize lipid de novo if the need arises, as in patients with LPL deficiency According to Sniderman et al. The increase of visceral fat masses with increasing total body fat was explained by an increase of fat cell size only up to a certain adipocyte weight.
However, with further enlargement of intraabdominal fat masses with severe obesity, the number of adipocytes seems to be elevated , In women, but not in men, omental adipose tissue has smaller adipocytes and lower LPL activity than subcutaneous fat depots since variations in LPL activity parallel differences in fat cell size 7.
When adipocytes enlarge in relation to a gain in body weight, the activity of LPL increases in parallel, possibly as a consequence of obesity-related hyperinsulinism. The higher basal activity of adipose tissue LPL in obesity is accompanied by a lower increment after acute hyperinsulinemia Lipid accumulation is favored in the femoral region of premenopausal women in comparison with men In the latter, LPL activity as well as the LPL mRNA levels were greater in the abdominal than in gluteal fat cells, while the opposite was observed in women, suggesting that regional variation of gene expression and posttranslational modification of LPL could potentially account for the differences between genders in fat distribution With progressive obesity, adipose tissue LPL is increased in the depots of fat in parallel with serum insulin.
However, when obese subjects lost weight and became less hyperinsulinemic, adipose LPL increased further and the patients who were most obese showed the largest increase in LPL, suggesting that very obese patients are most likely to have abnormal LPL regulation, independent of the influence of insulin.
In response to feeding, the increase in LPL is, as indicated, due to posttranslational changes in the LPL enzyme. However, the increased LPL after weight loss involved an increase in LPL mRNA levels, followed by parallel increases in LPL protein and activity Because the response to weight loss occurred via a different cellular mechanism, it is probably controlled by factors different from the day-to-day regulatory forces.
In addition, because the very obese patients demonstrated a larger increase in LPL with weight loss than the less obese patients, these data suggest a genetic regulation of LPL that is most operative in the very obese The role of sex steroids, glucocorticoids, and catecholamines in the regulation of adipose tissue LPL activity in various fat depots will be discussed in the section on hormonal regulation of abdominal visceral fat.
Lipid mobilization and the release of FFA and glycerol are modulated by the sympathetic nervous system. Catecholamines are the most potent regulators of lipolysis in human adipocytes through stimulatory β l - and β 2 -adrenoreceptors or inhibitoryα 2-adrenoreceptors A gene that codes for a third stimulatory β -adrenoreceptor, β 3 -adrenoreceptor, is functionally active principally in omental adipocytes but also present in mammary fat and subcutaneous fat in vivo In both genders and independently of the degree of obesity, femoral and gluteal fat cells exhibit a lower lipolytic response to catecholamines than subcutaneous abdominal adipocytes, the latter showing both increased β l - and β 2 -adrenoreceptor density and sensitivity and reduced α2-adrenoreceptor affinity and number Refs.
The increased sensitivity to catecholamine-induced lipolysis in omental fat in nonobese individuals is paralleled by an increase in the amount of β l - and β 2 -receptors, with normal receptor affinity and normal lipolytic action of agonists acting at postadrenoreceptor steps in the lipolytic cascade , ; this is associated with enhanced β 3 -adrenoreceptor sensitivity, which usually reflect changes in receptor number in comparison with subcutaneous adipocytes , Comparison of lipolysis, antilipolysis, and lipogenesis in omental and subcutaneous fat in nonobese and obese individuals.
Adipocytes from obese subjects generally show increased lipolytic responses to catecholamines, irrespective of the region from which they are obtained, and enhanced lipolysis in abdominal compared with gluteo-femoral fat 21 , The antilipolytic effect is also reduced in vitro in obesity, both in omental and subcutaneous adipocytes The typical features of visceral fat, e.
An increased β 3 -adrenoreceptor sensitivity to catecholamine stimulation may lead to an increased delivery of FFA into the portal venous system, with several possible effects on liver metabolism. These include glucose production, VLDL secretion, and interference with hepatic clearance of insulin , resulting in dyslipoproteinemia, glucose intolerance, and hyperisulinemia.
Lönnqvist et al. They observed that males had a higher fat cell volume with no sex differences in the lipolytic sensitivity to β l - and β 2 -adrenoreceptor-specific agonists or in the antilipolytic effect of insulin.
However, the lipolytic β 3 -adrenoreceptor sensitivity was 12 times higher in men, and the antilipolytic α2-adrenoreceptor sensitivity was 17 times lower in men.
It was concluded that in obesity, the catecholamine-induced rate of FFA mobilization from visceral fat to the portal venous system is higher in men than women. This phenomenon is partly due to a larger fat cell volume, a decrease in the function ofα 2-adrenoceptors, and an increase in the function of β 3 -adrenoreceptors.
These factors may contribute to gender-specific differences observed in the metabolic disturbances accompanied by obesity, i. Glucocorticoid receptors. Glucocorticoid receptors, one of the most important receptors for human adipose tissue function, are involved in metabolic regulation and distribution of body fat under normal as well as pathophysiological conditions.
Glucocorticoid receptors in adipose tissue show a regional variation in density with elevated concentrations in visceral adipose tissue In spite of the lower receptor density, the elevated cortisol secretion results in clearly increased net effects of cortisol.
Androgen and estrogen receptors. Adipocytes have specific receptors for androgens, with a higher density in visceral fat cells than in adipocytes isolated from subcutaneous fat. Unlike most hormones, testosterone induces an increase in the number of androgen receptors after exposure to fat cells , thereby affecting lipid mobilization.
This is more apparent in visceral fat omental, mesenteric, and retroperitoneal because of higher density of adipocytes and androgen receptors, in addition to other factors However, at variance with the effects of testosterone, dihydrotestosterone treatment does not influence lipid mobilization In females, there is an association between visceral fat accumulation and hyperandrogenicity, despite the documented effects of testosterone on lipid mobilization and the expected decrease in visceral fat depots.
The observation that visceral fat accumulation occurs only in female-to-male transsexuals after oophorectomy suggests that the remaining estrogen production before oophorectomy was protective The androgen receptor in female adipose tissue seems to have the same characteristics as that found in male adipose tissue.
However, estrogen treatment down-regulates the density of this receptor, which might be a mechanism whereby estrogen protects adipose tissue from androgen effects. Estrogen by itself seems to protect postmenopausal women receiving replacement therapy from visceral fat accumulation Estrogen receptors are expressed in human adipose tissue and show a regional variation of density, but whether the quantity of these receptors is of physiological importance has not been clearly established With regard to progesterone, adipose cells seem to lack binding sites and mRNA for progesterone receptors, indicating that progesterone acts through glucocorticoid receptors GH receptors.
While it is well established that GH has specific and receptor-mediated effects in adipose tissue of experimental animals, the importance of GH receptors in human adipose tissue is not fully elucidated at present although the available data indicate a functional role. However, GH is clearly involved in the regulation of visceral fat mass in humans.
Acromegaly, a state of GH excess, is associated with decreased visceral fat while in GH deficiency there is an increase in visceral fat and in adults with GH deficiency, recombinant human GH replacement therapy results in adipose tissue redistribution from visceral to subcutaneous locations; however, the regulation of adipose tissue metabolism requires synergism with steroid hormones A direct demonstration of a regulation of the GH receptor in human fat cells has not yet been performed Thyroid hormone receptors.
Thyroid hormones have multiple catabolic effects on fat cells as a result of interactions with the adrenergic receptor signal transduction system, and most of these interactions are also present in human fat cells There are data regarding the characterization of the nuclear T 3 receptor in human fat cells Although receptor regulation has not yet been demonstrated, there is little doubt that the thyroid hormone receptors are important for the function of human adipose tissue Further, no data are available on the correlation between visceral fat mass and thyroid hormone levels.
Adenosine receptors. Adenosine behaves as a potent antilipolytic and vasodilator agent and can be considered as an autocrine regulator of both lipolysis and insulin sensitivity in human adipose tissue.
Site differences in ambient adenosine concentration, perhaps controlled by blood flow, may also modulate adipose tissue metabolism 7.
Adenosine content is higher in omental than in abdominal subcutaneous adipose tissue, but the receptor-dependent inhibition of lipolysis is, as indicated before , less pronounced in the former than in the latter depot However, despite strong antilipolytic effect of adenosine analogs, human adipocytes contain few adenosine type A l receptors, regardless of the fat depot considered According to Arner , the α2-, β l -,β 2 -, and β 3 -adrenoreceptors and receptors for insulin, adenosine, and glucocorticoids, as well as for PGE 2 , a potent antilipolytic agent with high affinity receptors identified in adipocytes , have a major functional role, as shown by relevant biological receptor-mediated effects, the presence of a receptor molecule, and receptor regulation.
The receptors for GH, thyroid hormones, estrogen, and testosterone, as well as for acetylcholine and TSH, probably have an important functional role but complete evidence, indicated in the previous group of receptors, is not present so far; however, there is little doubt of a regulatory role.
Genetic epidemiology: heritability and segregation analysis. Studies performed in individuals from families of French descent living in Quebec City [Quebec Family Study QFS ] allowed the estimation of the fraction of the phenotypic variance that could be attributed to the genetic and environmental factors among the obesity phenotypes or in the distribution of the adipose tissue, taking into account the BMI and amount of subcutaneous fat by the sum of the measurement of skinfolds in six different sites , lean body mass, fat mass, percentage of fat derived from underwater weighing, and visceral fat by CT , The residual variance corresponded to environmental factors, but some factors cultural, nongenetic could be transmitted from parents to descendents and sometimes were confounded by genetic effects Segregation analysis studies have recently concluded that visceral fat is similarly influenced by a gene with a major effect in the QFS and HERITAGE families , However, after adjustment of the visceral adipose tissue for the fat mass, the effect of the gene with the major effect was not more compatible with a mendelian transmission.
These results suggested the presence of a pleiotropism: the gene with the major effect, identified by the fat mass , could similarly influence the amount of visceral fat Similar results were obtained with the same type of analysis in the HERITAGE cohort To test the hypothesis of a genetic pleiotropism, Rice et al.
The results of this study Fig. These results have confirmed the presence of a genetic pleiomorphism and suggested the presence of genes affecting simultaneously the amounts of fat mass and visceral abdominal fat.
Schematic representation of the genetic effects on total fat mass and visceral fat adjusted for the fat mass and on the co-variation between the two phenotypes Quebec Family Study, G 1 and G 2 represent the genetic effects specific for the total fat mass and visceral fat, respectively.
E 1 and E 2 represent the specific effects of the environment on total fat mass and visceral fat, respectively. G 3 and E 3 indicate the genetic and environment effects common to both phenotypes. Pérusse et al. The interactions of the effects of genotype and environment evaluated in monozygotic twins, when the energy balance is manipulated, indicated that even though there were large interindividual differences in the response to excess or negative energy balance, there was a significant within-pair resemblance in response 96 , In effect, in response to overfeeding, there was at least 3 times more variance in response between pairs than within pairs for the gains in body weight, fat mass, and fat-free mass In relation to the response to the negative energetic balance, at least 7 times more variation was observed in response between pairs than within members of the same pair of twins, with respect to the same variables This intrapair similarity in the response to either excess or deficient energy balance is also observed in relation to the abdominal visceral fat Thus, the interaction between genotype and environment is important to consider in the study of the genetics of obesity since the propensity to fat accumulation is influenced by the genetic characteristics of the subject.
Molecular genetics: association and linkage studies. Several candidate genes as well as random genetic markers were found to be associated with obesity as well as body fat and fat distribution in humans.
The current human obesity gene map, based on results from animal and human studies, indicates that all chromosomes, with the exception of the Y chromosome, include genes or loci potentially involved in the etiology of obesity Initial findings from the QFS showed that significant but marginal associations with body fat were found with LPL and the α2-subunit of the sodium-potassium ATPase genes The Trp64Arg mutation of the β 3 -adrenergic receptor gene β 3 AR , prevalent in some ethnic groups, is associated with visceral obesity and insulin resistance in Finns as well as increased capacity to gain weight This mutation was also shown to be associated with abdominal visceral obesity in Japanese subjects, with lower triglycerides in the Trp64Arg homozygotes but not heterozygotes It has been suggested that those with the mutation may describe a subset of subjects characterized by decreased lipolysis in visceral adipose tissue.
On the other hand, Vohl et al. Previously, it was reported by the same group that apo-B gene Eco R-1 polymorphism appeared to modulate the magnitude of the dyslipidemia generally found in the insulin-resistant state linked with visceral obesity These studies are a demonstration of a significant interaction between visceral obesity and a polymorphism for a gene playing an important role in lipoprotein metabolism.
When the genes related to the hormonal regulation of body fat distribution studied in the QFS families sex hormone-binding globulin, 3β-hydroxysteroid dehydrogenase, and glucocorticoid receptor genes were considered along with the knowledge that body fat distribution is influenced by nonpathological variations in the responsiveness to cortisol, it was shown that the less frequent 4.
However, the association with abdominal visceral fat area was seen only in subjects of the lower tertile of the percent body fat level. The consistent association between the glucocorticoid receptor polymorphism detected with Bcl I and abdominal visceral fat area suggested that this gene or a locus in linkage disequilibrium with the Bcl I restriction site may contribute to the accumulation of abdominal visceral adipose tissue With respect to the linkage studies, only a few studies of body fat or fat distribution with random genetic markers or candidate genes have been reported using the sibling-pair linkage method.
One of the few reported studies relative to the visceral fat mass was the evaluation of a sib-pair linkage analysis from the QFS between five microsatellite markers encompassing about 20 cM in the Mob-1 region of the human chromosome 16pp These results suggested to the authors that this region of the human genome contains a locus affecting the amount of visceral fat and lipid metabolism as also shown by the association studies indicated above.
The other population and intrafamily association study used a polymorphic marker LIPE in the hormone-sensitive lipase gene, located on chromosome 19q In conclusion, despite the fact that the genetic architecture of obesity has just begun, the results obtained so far suggest that a great number of genes, loci, or chromosomal regions distributed on different chromosomes could play a role in determining body fat and fat distribution in humans.
This reflects the complex and heterogeneous nature of obesity. The accumulation of adipose tissue in the abdominal region is at least partially influenced by genes, which becomes more evident as the number of involved genes are identified.
The concept that adipocytes are secretory cells has emerged over the past few years. Adipocytes synthesize and release a variety of peptide and nonpeptide compounds; they also express other factors, in addition to their ability to store and mobilize triglycerides, retinoids, and cholesterol.
These properties allow a cross-talk of adipose tissue with other organs as well as within the adipose tissue. The important finding that adipocytes secrete leptin as the product of the ob gene has established adipose tissue as an endocrine organ that communicates with the central nervous system.
As already mentioned, LPL is the key regulator of fat cell triglyceride deposition from circulating triglycerides. LPL is found, after transcytosis, associated with the glycosaminoglycans present in the luminal surface of the endothelial cells.
The regulation of LPL secretion, stimulated by the most important hormonal regulator, insulin, is related to posttranslational changes in the LPL enzyme, at the level of the Golgi cisternae and exocytotic vesicles, insulin possibly having a positive role in this secretory process Genes encoding LPL were not differentially expressed in omental when compared with subcutaneous adipocytes However, in very obese individuals omental adipocytes express lower levels of LPL protein and mRNA than do subcutaneous fat cells The regulation of LPL in obesity has been presented in the Section on correlations of abdominal visceral fat.
With respect to the hormonal regulation of LPL, insulin and glucocorticoids are the physiological stimulators of the LPL activity, and their association plays an important role in the regulation of body fat topography.
In effect, omental adipose tissue is known to be less sensitive to insulin, both in the suppression of lipolysis and in the stimulation of LPL However, when exposed to the combination of insulin plus dexamethasone in culture for 7 days, large increases in adipose LPL were observed because of increases in LPL mRNA Significant differences were observed between men and women.
The increase in LPL in response to dexamethasone suggests that the well known steroid-induced adipose redistribution especially in the abdomen may be caused by increases in LPL, which would lead to a preferential distribution of plasma triglyceride fatty acids to the abdominal depot.
Therefore, these data suggest that LPL is central to the development of abdominal visceral obesity On the other hand, catecholamines, GH, and testosterone in males reduce adipose tissue LPL Acylation-stimulating protein ASP.
ASP is considered the most potent stimulant of triglyceride synthesis in human adipocytes yet described. Its generation is as follows Human adipocytes secrete three proteins of the alternate complement pathway: C3 the third component of the complement , factor B, and factor D adipsin , which interact extracellularly to produce a amino-terminal fragment of C3 known as C3a.
Excess carboxypeptidases in plasma rapidly cleave the terminal arginine from C3a to produce the amino acid peptide known as C3a desarg or ASP, which then acts back upon the adipocyte, causing triglyceride synthesis to increase.
As fatty acids are being liberated from triglyceride-rich lipoproteins and chylomicrons as the result of the action of LPL, ASP is also being generated and triglyceride synthesis increased concurrent with the need to do so.
In human adipose tissue, in the postprandial period, ASP secretion and circulating triglycerides clearance are coordinated in accordance with the suggestion that ASP in sequence to LPL would have a paracrine autoregulatory role.
The adipsin-ASP pathway, therefore, links events within the capillary space to the necessary metabolic response in the subendothelial space, thus avoiding the excess buildup of fatty acids in the capillary lumen. The generation of ASP is triggered by chylomicrons. While insulin decreases gene expression of C3, B, and adipsin, it enhances the secretion of ASP as expected from the concurrent action of LPL and ASP.
However, more intensely and independent of insulin, ASP is capable of stimulating triglyceride synthesis in adipocytes and fibroblasts. Thus, from the reduced sensitivity to insulin in the suppression of lipolysis and stimulation of LPL by the omental adipose tissue, omental obesity may represent an example of impaired activity of the ASP pathway even if dysfunction of the pathway is a secondary feature.
As a consequence, omental adipose tissue, as compared with subcutaneous fat tissue, would have a limited capacity to prevent fatty acids from reaching the liver, which may contribute to the abnormalities in metabolism observed in visceral obesity Cholesteryl-ester transfer protein CETP.
Human adipose tissue is rich in CETP mRNA, probably one of the major sources of circulating CETP in humans. CETP promotes the exchange of cholesterol esters of triglycerides between plasma lipoproteins. In this way, the adipose tissue is a cholesterol storage organ in humans and animals; peripheral cholesterol is taken up by HDL species, which act as cholesterol efflux acceptors, and is returned to the liver for excretion , The few studies of circulating CETP in obesity have shown that activity and protein mass of CETP are both significantly increased in obesity, being negatively correlated with HDL cholesterol and the cholesteryl ester-triglyceride ratio of HDL2 and HDL3, thus exhibiting an atherogenic lipoprotein profile.
Furthermore, there was a positive correlation with fasting plasma insulin and blood glucose, suggesting a possible link to insulin resistance — From an observation of Angel and Shen , it could be suggested that the CETP activity of omental adipose tissue is greatly increased in comparison with subcutaneous fat.
Retinol-binding protein RBP. Adipose tissue is importantly involved in retinoid storage and metabolism. RBP is synthesized and secreted by adipocytes , the rate of RBP gene transcription being induced by retinoic acid The mRNA encoding RBP is expressed at a relatively high level in adipocytes with no difference between subcutaneous and omental fat cells There are no data regarding retinol mobilization from adipose stores in humans; however, in vitro studies with murine adipocytes showed that the cAMP-stimulated retinol efflux from fat cells was not the result of increased RBP secretion but instead due to the hydrolysis of retinyl esters by the cAMP-dependent hormone-sensitive lipase PAI-1 is a serine protease inhibitor and evidence suggests that it is a major regulator of the fibrinolytic system, the natural defense against thrombosis.
It binds and rapidly inhibits both single- and two-chain tissue plasminogen activator tPA and urokinase plasminogen activator uTPA , which modulate endogenous fibrinolysis.
The major sources of PAI-1 synthesis are hepatocytes and endothelial cells, but platelets, smooth muscle cells, and adipocytes are also contributors The increased gene expression and secretion of PAI-1 by adipose tissue contribute to its elevated plasma levels in obesity, presenting a strong correlation with parameters that define the insulin resistance syndrome, in particular with fasting plasma insulin and triglycerides, BMI, and visceral fat accumulation: omental adipose tissue explants produced significantly more PAI-1 antigen than did subcutaneous tissue from the same individual, and transforming growth factor-βl increased PAI-1 antigen production In a premenopausal population of healthy women with a wide range of BMI, there was a positive correlation of PAI-1 activity with CT-measured visceral fat area, independent of insulin and triglyceride levels.
Weight loss confirmed this link. PAI-1 diminution was correlated only with visceral adipose tissue area loss and not with total fat, insulin, or triglyceride decrease Results from in vitro studies have shown that insulin — stimulates PAI-1 production by cultured endothelial cells or hepatocytes.
Attempts to extrapolate these in vitro data to in vivo proved difficult. Acute 2-h hyperinsulinemia modulation of plasma insulin in humans did not affect PAI-1 levels, and hypertriglyceridemia from several origins was not always associated with increased PAI-1 levels In the same way, exogenous short-term insulin infusion with triacylglycerol and glucose failed to demonstrate elevations of PAI-1 The augmentation of PAI-1 by insulin probably requires concomitant elevation of lipids and glucose and perhaps other metabolites in blood, as suggested by the strikingly synergistic effects when Hep G2 cells are exposed to both insulin and fatty acids in vitro Accordingly, a hyperglycemic hyperinsulinemic clamp associated with an intralipid infusion for 6 h, to induce hyperinsulinemia combined with hyperglycemia and hypertriglyceridemia, produced an increase in PAI-1 concentrations in blood for as long as 6 h after cessation of the infusion However, the extent to which elevation of any one constituent or any given combination of elevations is sufficient to induce the phenomenon has not yet been elucidated in insulin-resistant patients.
In effect, the reduction of PAI-1 after weight loss related more to the degree of weight reduction than to triglyceride or insulin changes, as above indicated, and the lack of increase of PAI-1 in type 2 diabetics without obesity , strongly suggesting that visceral fat is an important contributor to the elevated plasma PAI-1 level observed in visceral obesity independent of insulin, triglyceride, and glucose level.
Finally, prospective cohort studies of patients with previous myocardial infarction or angina pectoris have underlined the association between an increase in plasma PAI-1 levels and corresponding defective fibrinolysis and the risk of atherosclerosis and thrombosis, particularly in relation to coronary events , thus linking visceral fat accumulation to macrovascular disease Recently, it was shown that in addition to insulin, corticosteroids dexamethasone and hydroxycorticosterone affect PAI-1 synthesis by human subcutaneous adipose tissue explants in a dose-dependent manner; this model showed the regulation of PAI-1 by adipose tissue after validation by showing a high correlation between the production of PAI-1 by omental and subcutaneous fat In the same way, it was demonstrated that PAI-1 production was significantly correlated with that of tumor necrosis factor-α TNFα , emphasizing a possible local contribution of TNFα in the regulation of PAI-1 production by human adipose tissue P aromatase activity in adipose tissue is important for estrogen production, which may have a paracrine role, since, as previously indicated, estrogen receptors are expressed in human adipose tissue In effect, estrone, the second major human circulating estrogen in premenopausal women and the predominant one in postmenopausal women, is mostly derived from the metabolism of ovarian-secreted estradiol catalyzed by 17β-hydroxy steroid dehydrogenase and from aromatization of androstenedione in adipose tissue in the former and almost exclusively by aromatization of that C19 androgen secreted by the adrenals in the latter.
The peripheral aromatization of testosterone to estradiol and estrone contributes minimally to estradiol and estrone production The conversion rate of androstenedione to estrone increases as a function of aging and obesity [due to an increase in adipose tissue P aromatase transcript levels, highest in the buttocks, next highest in the thighs, and lowest in the subcutaneous abdominal tissue , ] and significantly greater in women with lower gynoid obesity than in upper body obesity In obese men, the peripheral conversions of testosterone to estradiol and androstenedione to estrone, as well as the circulating levels of those estrogens, are also increased in proportion to the degree of obesity , However, only plasma levels of estrone had a significant correlation with CT-derived abdominal visceral fat and femoral areas Since the increased metabolism of testosterone to estradiol did not account for the major increase in estradiol production in obese men , it is probable that estradiol is secreted or is produced from the peripheral conversion of estrone, as observed in postmenopausal women.
The most abundant adrenal steroid, dehydroepiandrosterone sulfate DHEA-S can also form the active sex steroids, dihydrotestosterone and estradiol, in several tissues, including mesenteric fat The active androgens and estrogens made locally in peripheral tissues, especially adipose fat, exert their action by interacting with the corresponding receptors in the same or nearby cells where their synthesis took place before being released in the extracellular environment as such or as inactive metabolites.
The aromatase enzyme responsible for transforming androstenedione into estrone is present in nonendocrine tissues, particularly adipocytes and adipose stromal cells, the level of aromatase activity in stromal cells being greater than that in adipocytes Insulin and cortisol independently induce preadipocyte differentiation with both having a synergistic effect The intrinsic gender differences in preadipocytes could contribute to a gender-specific pattern of fat distribution Leptin is the product of the obesity ob gene, which is expressed in adipocytes , The human ob gene spans approximately 20 kb and exists in a single copy on chromosome 7q Several studies in rodents suggest that leptin acts as a signaling factor from adipose tissue to the central nervous system, regulating food intake and energy expenditure.
It is hypothesized that via this leptin feedback loop, homeostasis of body weight and a constant amount of body fat are achieved In humans, a strong positive correlation is observed between serum leptin levels and the amount of body fat and adipocyte leptin mRNA as in rodents , The results are in accordance with the in vitro data indicating that leptin secretion is a reflection of fat hypertrophy.
The adipocyte is the only known source of the ob gene product, leptin, as the preadipocytes do not present this capacity The subcutaneous-omental ratio of leptin mRNA expression was markedly higher in women than in men.
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