Role of the Gut in Visceral Fat Inflammation and Metabolic Disorders

NAFLD, Obesity, and Bariatric Surgery

Abdominal fat distribution and insulin resistance in Indian women with polycystic ovarian syndrome

Background: Hypertension and obesity are very common and complex cardiovascular (CV) risk factors. Our aim was to provide a comprehensive assessment of associations between visceral fat depots and vascular or cardiac complications of hypertension. Methods: All the consecutive patients (age: 45-80 years old) scheduled for elective coronary angiography in the Department of Cardiology were screened, and 400 patients were included into the study group. All the patients had a comprehensive clinical assessment focused on hypertension and obesity, risk factors, fat depots, and several hypertension-related vascular or cardiac complications. Results: The study group (n = 400; F/M: 140/260; age: 61 ± 7 years) included patients with hypertension (n = 354; 88.5%) and normal blood pressure (n = 46; 11.5%) and individuals with obesity (n = 192; 48%), diabetes (n = 139; 35%), metabolic syndrome (n = 240; 60%), and coronary artery disease (n = 286; 71%). Patients with higher degrees of hypertension (grade 3 vs. 2 vs. 1) showed increased body mass index (BMI) and waist circumference and ultrasound indexes of perivascular, epicardial, and abdominal visceral fat with no differences in age, waist-hip ratio, and subcutaneous fat. Both visceral fat depots: perivascular fat (carotid extra-media thickness) and abdominal visceral fat (intra-abdominal thickness) assessed as single measures and ratios were significantly increased in hypertensive patients with high versus low global CV risk in a hypertension-focused risk model (differences more pronounced in patients ≤60 years old). Visceral fat parameters were not independent, but rather additive to general obesity (BMI), except for visceral abdominal fat depot. Conclusions: Visceral abdominal and perivascular fat depots assessed as ultrasound indexes are associated with complications of hypertension and CV risk indicators, especially in patients with a mild-to-moderate hypertension and in younger patients.

The prevalence of obesity in the United States and the world has risen to epidemic/pandemic proportions. This increase has occurred despite great efforts by healthcare providers and consumers alike to improve the health-related behaviors of the population and a tremendous push from the scientific community to better understand the pathophysiology of obesity. This epidemic is all the more concerning given the clear association between excess adiposity and adverse health consequences such as cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). The risks associated with overweight/obesity are primarily related to the deposition of adipose tissue, which leads to excess adiposity or body fatness. Furthermore, weight loss, specifically loss of body fat, is associated with improvement in obesity-related comorbidities. Before weight loss interventions can be recommended, however, patients must be assessed for their adiposity-related risk. Unfortunately, healthcare providers and systems have not done a good job of assessing for excess adiposity even in its simplest form, such as measuring body mass index (BMI). It is for these reasons that we must emphasize the importance of assessing adiposity in clinical practices. Although it can be argued that the entire population should be targeted as an important public health issue with a goal of prevention of weight gain and obesity, there are currently so many “at risk” individuals that simple strategies to identify and treat those individuals are necessary. We must identify those individuals at highest risk of comorbidities in order to identify those who might benefit the most from aggressive weight management. This scientific statement will first briefly review the epidemiology of obesity and its related comorbidities, supporting the need for improved assessment of adiposity in daily clinical practice. This will be followed by a discussion of some of the challenges and issues associated with assessing adiposity and then by a review …

BackgroundObesity‐associated metabolic disorders have been shown to be related to body fat distribution. Specifically, increases in visceral fat are more detrimental than increases in subcutaneous fat depots. However, the underlying mechanisms through which visceral fat potentiates cardiometabolic dysregulation are not completely understood. In recent years, the presence of localized renin angiotensin system (RAS) in adipose tissue and its role in regulating blood pressure and metabolism has been recognized. Therefore, we investigated if differential expression of RAS components in visceral versus subcutaneous adipose tissue may help explain pathological effects of visceral fat.HypothesisWe hypothesized that compared to subcutaneous adipose tissue, visceral adipose tissue has increased expression of RAS proteins involved in the pro‐inflammatory and pro‐fibrotic ANGII‐AT1R pathway but attenuated expression of proteins mediating the anti‐inflammatory and anti‐fibrotic ANG1‐7‐MASR pathway.MethodsWe determined the expression of RAS proteins in paired subcutaneous and visceral (omental) adipose tissue samples from obese individuals undergoing surgery (n = 30, BMI: 46.1 ± 7.3 kg/m2, age: 46.5 ± 14.4 years) by Western blot. We examined proteins involved in 1) Ang II generation: angiotensinogen (AGT), angiotensin converting enzyme (ACE), chymase; 2) Ang1‐7 generation: ACE‐2; and 3) cellular receptors: angiotensin I receptor (AT1R), MAS receptor (MASR), and aldosterone receptor.ResultsComparison of protein expression between subcutaneous and visceral adipose tissue samples showed no changes in proteins involved in generation of angiotensin peptides, namely AGT (0.64 ± 0.57 vs. 0.33 ± 0.28, p = 0.11, n = 12), chymase (0.27 ± 0.23 vs. 0.36 ± 0.41, p = 0.77, n = 22), and ACE‐2 (0.23 ± 0.41 vs. 0.08 ± 0.09, p = 0.21, n = 15). However, ACE expression tended to be higher in subcutaneous vs. visceral fat (0.10 ± 0.06 vs. 0.06 ± 0.03, p = 0.052, n = 12). Furthermore, expression of cellular receptor AT1R was higher in subcutaneous fat (0.24 ± 0.34 vs. 0.07 ± 0.09, p = 0.03, n = 12), and MASR was lower in subcutaneous fat (0.22 ± 0.26 vs. 0.88 ± 0.99, p = 0.01, n = 20). Aldosterone receptor expression (0.21 ± 0.22 vs. 0.14 ± 0.13, p = 0.52, n = 11) was not altered in subcutaneous and visceral depots.ConclusionsProteins involved in the generation of angiotensin peptides are not differentially expressed in subcutaneous versus visceral fat depots. However, expression of cellular receptors is different such that inflammatory and fibrotic effects of RAS may be more predominant in subcutaneous fat. Therefore, RAS is likely to play a role in limiting subcutaneous fat expansion thereby leading to increased visceral fat depots. Furthermore, our findings do not support the role of visceral RAS in development and progression of cardiovascular pathology associated with increased visceral fat depots.Support or Funding InformationMAP and KRS were supported by the American Physiological Society Stride Summer Undergraduate Research Fellowship NHLBI 1 R25 HL115473‐01.

Obesity, and more specifically accumulation of adipose tissue in the visceral and subcutaneous abdominal locations, is a major risk factor for the development of cardiovascular pathologies including hypertension and atherosclerosis, as well as metabolic disorders such as type 2 diabetes. During recent years, “metaflammation” or metabolically-triggered inflammation1 has emerged as a key process involved in the clustering of those conditions. Although several metabolically active organs such as the liver, muscle, and, recently, the intestine2 certainly play major roles, the white adipose tissue appears as a central and primary player as both a source and site of inflammation. Accumulation of adipose tissue macrophages (ATMs) has been well-described in obese conditions in mice and humans.3–5 Moreover, the ATM proinflammatory phenotype has been linked to the development of insulin resistance in mice,4 although the exact nature of the proinflammatory myeloid cells, ie, macrophages or dentritic cells, remains to be determined.6 Nevertheless, the causal link between inflammation and insulin resistance was further strengthened by the specific knock-out of the inflammation coordinator IkappaB kinase beta of myeloid cells, which gave protection against insulin resistance.7 The study of Kintscher and al in this issue8 extends those original observations to cells of adaptative immunity. The authors suggest that the accumulation of T-lymphocytes, assessed mainly through gene expression analyses and immunohistochemistry, occurs in the perigonadal adipose tissue of mice on …

Visceral fat, notably mesenteric fat, which is drained by the portal circulation, plays a critical role in the pathogenesis of metabolic syndrome through increased production of free fatty acids, cytokines and vasoactive peptides. We hypothesize that mesenteric fat thickness as measured by ultrasound scan could explain most of the obesity-related health risk. We explored the relationships between cardiovascular risk factors and abdominal fat as determined by sonographic measurements of thickness of mesenteric, preperitoneal and subcutaneous fat deposits, total abdominal and visceral fat measurement by magnetic resonance imaging (MRI) and anthropometric indexes. A cross-sectional study. Subjects included 18 healthy men and 19 women (age: 27-61 y, BMI: 19-33.4 kg/m(2)). The maximum thickness of mesenteric, preperitoneal and subcutaneous fat was measured by abdominal ultrasound examination. MRI examinations of whole abdomen and pelvis were performed and the amount of total abdominal and visceral fat was quantified. The body mass index, waist circumference and waist-hip ratio were recorded. Cardiovascular risk factors were assessed by physical examination and blood taking. Men had more adverse cardiovascular risk profile, higher visceral fat volume and thicker mesenteric fat deposits than women. Among all the investigated obesity indexes, the mesenteric fat thickness showed the highest correlations with total cholesterol, LDL-C, triglycerides, fasting plasma glucose, HbA(1c) and systolic blood pressure in men, and with triglycerides and HbA(1c) in women. On stepwise multiple regression analysis with different obesity indexes as independent variables, 30-65% of the variances of triglycerides, total cholesterol, LDL-C and HbA(1c) in men, and triglycerides in women were explained by the mesenteric fat thickness. Compared with sonographic measurement of subcutaneous and preperitoneal fat thickness, MRI measurement of total abdominal and visceral fat and anthropometric indexes, sonographic measurement of mesenteric fat thickness showed better associations with some of the cardiovascular risk factors. It may potentially be a useful tool to evaluate regional distribution of obesity in the assessment of cardiovascular risk.

Adipose tissue plays a critical role in energy homeostasis and metabolism. There is sparse understanding of the molecular regulation at the protein level of bovine adipose tissues, especially within different fat depots under different nutritional regimes. The objective of this study was to analyze the differences in protein expression between bovine subcutaneous and visceral fat depots in steers fed different diets and to identify the potential regulatory molecular mechanisms of protein expression. Subcutaneous and visceral fat tissues were collected from 16 British-continental steers (15.5 month old) fed a high-fat diet (7.1% fat, n=8) or a control diet (2.7% fat, n=8). Protein expression was profiled using label free quantification LC-MS/MS and expression of selected transcripts was evaluated using qRT-PCR. A total of 682 proteins were characterized and quantified with fat depot having more impact on protein expression, altering the level of 51.0% of the detected proteins, whereas diet affected only 5.3%. Functional analysis revealed that energy production and lipid metabolism were among the main functions associated with differentially expressed proteins between fat depots, with visceral fat being more metabolically active than subcutaneous fat as proteins associated with lipid and energy metabolism were upregulated. The expression of several proteins was significantly correlated to subcutaneous fat thickness and adipocyte size, indicating their potential as adiposity markers. A poor correlation (r=0.245) was observed between mRNA and protein levels for 9 genes, indicating that many proteins may be subjected to post-transcriptional regulation. A total of 8 miRNAs were predicted to regulate more than 20% of lipid metabolism proteins differentially expressed between fat depots, suggesting that miRNAs play a role in adipose tissue regulation. Our results show that proteomic changes support the distinct metabolic and physiological characteristics observed between subcutaneous and visceral adipose tissue depots in cattle.

Characterization of TGF-β expression and signaling profile in the adipose tissue of rats fed with high-fat and energy-restricted diets

Feed restriction alters lipogenic and adipokine gene expression in visceral and subcutaneous fat depots in lamb

Diet-related obesity is a major metabolic disorder. Excessive fat mass is associated with type 2 diabetes, hepatic steatosis, and arteriosclerosis. Dysregulation of lipid metabolism and adipose tissue function contributes to diet-induced obesity. Here, we report that β-arrestin-1 knock-out mice are susceptible to diet-induced obesity. Knock-out of the gene encoding β-arrestin-1 caused increased fat mass accumulation and decreased whole-body insulin sensitivity in mice fed a high-fat diet. In β-arrestin-1 knock-out mice, we observed disrupted food intake and energy expenditure and increased macrophage infiltration in white adipose tissue. At the molecular level, β-arrestin-1 deficiency affected the expression of many lipid metabolic genes and inflammatory genes in adipose tissue. Consistently, transgenic overexpression of β-arrestin-1 repressed diet-induced obesity and improved glucose tolerance and systemic insulin sensitivity. Thus, our findings reveal that β-arrestin-1 plays a role in metabolism regulation.

Abdominal obesity has been linked to the development of insulin resistance and Type 2 diabetes mellitus (DM2). By surgical removal of visceral fat (VF) in a variety of rodent models, we prevented insulin resistance and glucose intolerance, establishing a cause-effect relationship between VF and the metabolic syndrome. To characterize the biological differences between visceral and peripheral fat depots, we obtained perirenal visceral (VF) and subcutaneous (SC) fat from 5 young rats. We extracted mRNA from the fat tissue and performed gene array hybridization using Affymetrix technology with a platform containing 9 000 genes. Out of the 1 660 genes that were expressed in fat tissue, 297 (17.9 %) genes show a two-fold or higher difference in their expression between the two tissues. We present the 20 genes whose expression is higher in VF fat (by 3 - 7 fold) and the 20 genes whose expression is higher in SC fat (by 3 - 150 fold), many of which are predominantly involved in glucose homeostasis, insulin action, and lipid metabolism. We confirmed the findings of gene array expression and quantified the changes in expression in VF of genes involved in insulin resistance (PPARgamma leptin) and its syndrome (angiotensinogen and plasminogen activating inhibitor-1, PAI-1) by real-time PCR (qRT-PCR) technology. Finally, we demonstrated increased expression of resistin in VF by around 12-fold and adiponectin by around 4-fold, peptides that were not part of the gene expression platform. These results indicate that visceral fat and subcutaneous fat are biologically distinct.

The aim of this study was to evaluate the association of abdominal visceral and subcutaneous fat, independent of total body fat, with cardiometabolic risk factors and insulin resistance among youth. Visceral and subcutaneous fat, percentage total body fat, insulin resistance (adjusted for lean body mass: Mlbm), blood pressure, glucose, insulin and lipids were obtained in 472 youth ages 6-18 years. Linear regression, adjusted for age, sex, race, Tanner stage and percentage total body fat, was used to evaluate associations of visceral and subcutaneous fat with cardiometabolic risk factors. Visceral fat was associated inversely with Mlbm (P = 0.003) and positively with fasting insulin (P = 0.002) and triglycerides (P = 0.002). Visceral fat levels above the mean were associated inversely with high-density lipoprotein (HDL) cholesterol (P = 0.002), and positively with systolic blood pressure (P < 0.0001) and non-HDL cholesterol (P < 0.0001). Subcutaneous fat was associated inversely with Mlbm (P = 0.003) and HDL cholesterol (P < 0.05), and positively with fasting glucose (P < 0.05), fasting insulin (P = 0.0003), systolic blood pressure (P = 0.005) and triglycerides (P = 0.003). Subcutaneous fat levels above the mean were associated with non-HDL cholesterol (P = 0.0002). These findings suggest that there may be a threshold level of visceral and subcutaneous fat (regardless of total body fat), that when exceeded in childhood, is more likely to be associated with many cardiometabolic risk factors. Triglycerides and insulin resistance appear to be associated with these fat depots at even lower thresholds of abdominal adiposity.

Retinol binding protein 4 (RBP4) is a novel adipokine which might be involved in the development of insulin resistance. The aim of the study was to investigate the expression of RBP4 mRNA in subcutaneous and visceral fat depots and the relationship between RBP4 plasma and mRNA levels relative to indices of adiposity and insulin resistance. In 59 Caucasian women (BMI 20 to 49 kg/m(2)) paired samples of subcutaneous and visceral fat were obtained for RBP4, leptin and GLUT 4 mRNA analysis using reverse transcription-quantitative PCR. Euglycemic hyperinsulinemic clamp and computed tomography scans were performed. RBP4 mRNA levels as well as GLUT 4 mRNA and leptin mRNA levels were lower (P<0.001, P<0.01 and P<0.001, respectively) in visceral compared to subcutaneous fat. No differences were found in RBP4 mRNA expression in the two fat depots or in RBP4 plasma levels between subgroups of non-obese subjects (n=26), obese subjects without metabolic syndrome (n=17) and with metabolic syndrome (n=16). No correlations between RBP4 mRNA or plasma levels relative to adiposity, glucose disposal rate and GLUT 4 mRNA expression in adipose tissue were found. There was a weak positive correlation between plasma RBP4 and plasma triglycerides (r = 0.30, p<0.05) and between plasma RBP4 and blood glucose (r = 0.26, p<0.05). Regardless of the state of adiposity or insulin resistance, RBP4 expression in humans was lower in visceral than in subcutaneous fat. We found no direct relationship between either RBP4 mRNA or its plasma levels and the adiposity or insulin resistance.

Mammals possess fat in three distinct depots- brown, subcutaneous and visceral fat depots. While brown fat contains thermogenic brown fat cells, the subcutaneous and visceral fat depots contain lipid-storing white fat cells. Excess visceral fat is associated with increased insulin resistance and type 2 diabetes, whereas the presence of brown fat corelates with lower odds of type 2 diabetes. These differences likely arise due to distinct developmental origins of brown and white fat cells. Expression of co-factors such as PRDM16 and PGC1α is limited to brown fat cells. Brown and white fat cells also have distinct sets of open chromatin. I hypothesize that epigenetic variations between brown and white fat can reveal fat depot-enriched factors that are essential to establishing fat identity and phenotype, and therefore, influence obesity and type 2 diabetes. Adipoq-NuTrap mice, that have labeled adipocytes, were used to isolate adipocyte nuclei from brown and visceral fat. ATAC-sequencing of these nuclei uncovered fat cell-specific open regions, which were then subjected to bioinformatic analysis to identify depot-enriched transcription factors. These analyses resulted in the discovery of two factors: Arx and Nr2f6. Arx is dramatically enriched in visceral gonadal fat, compared to brown and subcutaneous fat. Pathway analysis of Arx target genes reveal that Arx may regulate inflammation, cell shape and motility. Adipose-specific Arx knockout mice have lesser visceral fat and will be used to study the role of Arx in insulin tolerance and obesity. On the other hand, Nr2f6 expression is enriched in brown fat, increases with cold exposure and is dependent on PRDM16 expression. Pathway analysis of Nr2f6 target genes show that Nr2f6 regulates mitochondrial, thermogenic and lipolytic genes, genes central to brown fat function. Nr2f6 overexpression dampened thermogenic response, suggesting a novel regulatory mechanism in brown fat function. Nr2f6-null mice will be used to assess the role of Nr2f6 in brown fat function. Disclosure A. Maganti: None. J. Chi: None. P. Cohen: None. Funding American Diabetes Association (1-19-PDF-024 to A.M.)