Subcutaneous fat and diabetes risks -
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Medical News Today. Health Conditions Health Products Discover Tools Connect. Reversing diabetes: Visceral fat more important than overall weight.
By Timothy Huzar on September 30, — Fact checked by Jessica Beake, Ph. Share on Pinterest According to a small study, even people of moderate weight can reverse diabetes by losing visceral fat. Type 2 diabetes. Weight loss without overweight?
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Scientists discover biological mechanism of hearing loss caused by loud noise — and find a way to prevent it. How gastric bypass surgery can help with type 2 diabetes remission. Atlantic diet may help prevent metabolic syndrome. Some clinical studies have dissociated the glucose metabolic effects of visceral adiposity from hepatic lipid accumulation.
In one such study, significant differences in insulin sensitivity in the liver, skeletal muscle, and adipose tissue were reported in obese human subjects who differed in hepatic lipid content, with no such differences observed in obese subjects who differed in visceral adiposity Similarly, in a study in which obese subjects were matched for liver fat content, no differences in indices of glucose metabolism were noted Insulin-sensitive MHO individuals tend to have lower visceral and intrahepatic fat accumulation than their MUHO counterparts , , , providing further evidence that these fat depots contribute to insulin resistance.
Collectively, while visceral adiposity and hepatic fat content are both strongly associated with whole-body and tissue-specific insulin resistance, hepatic lipid accumulation may play a more direct role in negatively modulating glucose homeostasis.
Many studies have suggested that fat distribution is strongly associated with insulin resistance, with visceral adiposity being the strongest predictor of insulin resistance , , While the detrimental effects of visceral and hepatic lipid accumulation on glucose metabolism are clear, it is also becoming increasingly appreciated that lower body subcutaneous adiposity may be metabolically protective — Large-volume liposuction of subcutaneous WAT has shown little to no metabolic benefit in human trials 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.
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It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Endocrine Society Journals. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract.
Subjects and Methods. Journal Article. Metabolic Effects of Visceral Fat Accumulation in Type 2 Diabetes. Amalia Gastaldelli , Amalia Gastaldelli. Oxford Academic. Yoshinori Miyazaki. Maura Pettiti. Masafumi Matsuda. Srihanth Mahankali. Eleonora Santini. Ralph A. Ele Ferrannini. PDF Split View Views.
Cite Cite Amalia Gastaldelli, Yoshinori Miyazaki, Maura Pettiti, Masafumi Matsuda, Srihanth Mahankali, Eleonora Santini, Ralph A. Select Format Select format.
ris Mendeley, Papers, Zotero. enw EndNote. bibtex BibTex. txt Medlars, RefWorks Download citation. Permissions Icon Permissions. Abstract Visceral fat VF excess has been associated with decreased peripheral insulin sensitivity and has been suggested to contribute to hepatic insulin resistance.
Table 1. Group 1. Group 2. Group 3. group 1 and. group 2 by Bonferroni-Dunn test. Open in new tab. Table 2. Univariate correlation between metabolic and anthropometric variables.
Male sex. SF area. VF area. Male sex 0. MCR, Metabolic clearance rate. Figure 1. Open in new tab Download slide. Table 3. a P value for the difference among groups after adjustment by sex, age, ethnicity, BMI, and sulfonylurea treatment.
group 2 by contrasts. Table 4. Figure 2. gas chromatography-mass spectrometry;. Lilly lecture Google Scholar Crossref. Search ADS. Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake.
Role of hepatic glucose production and glucose uptake in the pathogenesis of fasting hyperglycemia in type 2 diabetes: normalization of glucose kinetics by short-term fasting. Google Scholar PubMed. OpenURL Placeholder Text.
Tisks a small, diaabetes study, researchers have Subcutaneoks that people Body composition optimization type Nutritional facts diabetes who Subcutanwous have a BMI that falls within a disbetes range can Body composition optimization their diabetes by losing weight. Sucbutaneous researchers diabetrs their findings at the Annual Meeting of the Rissks Association for the Study Bodyweight assessment Diabetes. Type 2 diabetes is the most common form of diabetes, accounting for around Insulin normally helps glucose enter the cells of the body. In the absence of insulin, glucose stays in the blood, where it can damage organs and tissues. This means that a person with type 2 diabetes has an increased risk of several health issues, including stroke, heart disease, issues with their feet, kidney disease, dental issues, and bladder problems. According to researchers writing in the journal Nutrientsscientists for a long time believed that type 2 diabetes was incurable, so they primarily focused on how people should manage symptoms of the condition.
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