White Adipose Tissue Depots Research Articles

Giant mice reveal new roles for GH in regulating the adipose immune microenvironment.

Giant mice reveal new roles for GH in regulating the adipose immune microenvironment.

Inflammation and the depot-specific secretome of human preadipocytes.

Visceral white adipose tissue (WAT) expansion and macrophage accumulation are associated with metabolic dysfunction. Visceral WAT typically shows greater macrophage infiltration. Preadipocytes show varying proinflammatory expression profiles among WAT depots. The objective was to examine the secretomes and chemoattractive properties of preadipocytes from visceral and subcutaneous WAT. A label-free quantitative proteomics approach was applied to study secretomes of subcutaneous and omental preadipocytes from obese subjects. Enzyme-linked immunosorbent assays and chemotaxis assays were used to confirm proinflammatory chemokine secretion between depots. Preadipocyte secretomes showed greater variation between depots than did intracellular protein expression. Chemokines were the most differentially secreted proteins. Omental preadipocytes induced chemoattraction of macrophages and monocytes. Neutralizing antibodies to the identified chemokines reduced macrophage/monocyte chemoattraction. Subcutaneous preadipocytes treated with interleukin-6 (IL-6) resembled omental preadipocytes in terms of chemokine secretion and macrophage/monocyte chemoattraction. Janus-activated kinase (JAK1/2) protein expression, which transduces IL-6 signaling, was higher in omental than subcutaneous preadipocytes and WAT. Inhibiting JAK in omental preadipocytes decreased chemokine secretion and macrophage/monocyte chemoattraction to levels closer to that observed in subcutaneous preadipocytes. Secretomes of omental and subcutaneous preadipocytes are distinct, with the former inducing more macrophage/monocyte chemoattraction, in part through IL-6/JAK-mediated signaling.

Disequilibrium of polyunsaturated fatty acids status and its dual effect in modulating adipose tissue development and functions

White adipocytes are storing energy under the form of triglycerides whereas brown adipocytes dissipate energy from triglycerides by producing heat. In rodents and possibly in humans both types of fat cells participate in the total energy balance. From a quantitative view point, a positive energy balance (energy intake > energy expenditure) is commonly regarded as a major factor contributing to obesity. Recent studies demonstrate that by altering rates of adipocyte differentiation and proliferation, differences in fatty acid composition of dietary fats may also contribute to adipose tissue development, in particular with respect to the relative intake of ω 6 to ω 3 poly-unsaturated fatty acids (PUFAs). The ω 6/ω 3 ratio determines the availability of ω 6-arachidonic acid (ARA) within adipose tissue and thus the level of various prostaglandins derived from the cyclooxygenase-mediated pathway. We had shown earlier that prostacyclin (Prostaglandin I2) stimulates fat cell differentiation and this effect could be reversed by ω 3-PUFA supplementation. Moreover, we had assessed that under conditions of genome stability a Western-like fat diet rich in ω 6-PUFA was sufficient to induce a gradual fat mass enhancement across generations. Recently, we have characterized a second effect of some ARA metabolites (prostaglandins E2 and F2α ) which appear to inhibit the formation of brown adipocytes within white adipose tissue. Altogether, our results demonstrate that, in addition to favoring white adipose tissue formation, dietary excess of ω 6-PUFA prevents the “browning” process to take place in white adipose tissue depots, and strongly suggest a favorable role of ω 3-PUFA supplementation in preventing both processes.

Activation of natriuretic peptides and the sympathetic nervous system following Roux-en-Y gastric bypass is associated with gonadal adipose tissues browning.

ObjectiveRoux-en-Y gastric bypass (RYGB) is an effective method of weight loss and remediation of type-2 diabetes; however, the mechanisms leading to these improvements are unclear. Additionally, adipocytes within white adipose tissue (WAT) depots can manifest characteristics of brown adipocytes. These ‘BRITE/beige’ adipocytes express uncoupling protein 1 (UCP1) and are associated with improvements in glucose homeostasis and protection from obesity. Interestingly, atrial and B-type natriuretic peptides (NPs) promote BRITE/beige adipocyte enrichment of WAT depots, an effect known as “browning.” Here, we investigate the effect of RYGB surgery on NP, NP receptors, and browning in the gonadal adipose tissues of female mice. We propose that such changes may lead to improvements in metabolic homeostasis commonly observed following RYGB.MethodsWild type, female, C57/Bl6 mice were fed a 60% fat diet ad libitum for six months. Mice were divided into three groups: Sham operated (SO), Roux-en-Y gastric bypass (RYGB), and Weight matched, sham operated (WM-SO). Mice were sacrificed six weeks following surgery and evaluated for differences in body weight, glucose homeostasis, adipocyte morphology, and adipose tissue gene expression.ResultsRYGB and calorie restriction induced similar weight loss and improved glucose metabolism without decreasing food intake. β3-adrenergic receptor expression increased in gonadal adipose tissue, in addition to Nppb (BNP), and NP receptors, Npr1, and Npr2. The ratio of Npr1:Npr3 and Npr2:Npr3 increased in RYGB, but not WM-SO groups. Ucp1 protein and mRNA, as well as additional markers of BRITE/beige adipose tissue and lipolytic genes increased in RYGB mice to a greater extent than calorie-restricted mice.ConclusionsUpregulation of Nppb, Npr1, Npr2, and β3-adrenergic receptors in gonadal adipose tissue following RYGB was associated with increased markers of browning. This browning of gonadal adipose tissue may underpin the positive effect of RYGB on metabolic parameters and may in part be mediated through upregulation of natriuretic peptides.

White Adipose Tissue Depot-Specific Activity of Lipogenic Enzymes in Response to Fasting and Refeeding in Young and Old Rats

Background: Although the heterogeneity of white adipose tissue (WAT) in different anatomical sites is a well-known phenomenon, there are scarce data on aging-associated metabolic alterations in various WAT depots. Objective: We used the model of fasting and refeeding to analyze the effect of aging on the activity of key lipogenic enzymes in retroperitoneal (rWAT), epididymal (eWAT), and subcutaneous (sWAT) adipose tissue depots. Methods: 5- and 24-month-old male Wistar rats were fasted for 48 h or were fasted for 2 days and subsequently refed for 2 or 4 days. Control animals had ad libitum access to chow. Samples obtained from three WAT deposits were analyzed for the enzymatic activities of ATP citrate lyase (ACL), fatty acid synthase (FAS), and glucose-6-phosphate dehydrogenase (G6PD). Concentrations of lipids and proteins were measured in the blood serum. Results: Fasting for 2 days decreased the concentration of free fatty acids only in the young rats. The basal activities of ACL and FAS were lower in eWAT than in rWAT and sWAT of the young rats. In the young rats, fasting did not change ACL and FAS activities in any of the studied depots. Refeeding increased these activities more quickly in rWAT than in eWAT, while in sWAT no induction was observed. ACL and FAS activities were manifold lower in all WAT depots of the old than in those of the young rats. In the old animals fasting had no effect on ACL activity in any depot and decreased FAS activity only in sWAT. After 4 days of refeeding, FAS activity increased in rWAT and sWAT, but no change in ACL activity occurred. G6PD activity in the young rats was lower by 40% in eWAT than in rWAT. The induction of the enzyme by refeeding occurred faster in rWAT than in eWAT, while in sWAT no change in G6PD activity was observed. G6PD activity did not change with aging. Fasting of the old rats decreased G6PD activity in rWAT and sWAT. Refeeding failed to induce the enzyme in these depots, whereas in eWAT G6PD activity increased by 76% after 4 days of refeeding. Conclusion: Fasting and refeeding revealed WAT depot-specific, age-related changes of the activities of lipogenic enzymes.

Oxygen deprivation and the cellular response to hypoxia in adipocytes - perspectives on white and brown adipose tissues in obesity.

Relative hypoxia has been shown to develop in white adipose tissue depots of different types of obese mouse (genetic, dietary), and this leads to substantial changes in white adipocyte function. These changes include increased production of inflammation-related adipokines (such as IL-6, leptin, Angptl4, and VEGF), an increase in glucose utilization and lactate production, and the induction of fibrosis and insulin resistance. Whether hypoxia also occurs in brown adipose tissue depots in obesity has been little considered. However, a recent study has reported low pO2 in brown fat of obese mice, this involving mitochondrial loss and dysfunction. We suggest that obesity-linked hypoxia may lead to similar alterations in brown adipocytes as in white fat cells – particularly changes in adipokine production, increased glucose uptake and lactate release, and insulin resistance. This would be expected to compromise thermogenic activity and the role of brown fat in glucose homeostasis and triglyceride clearance, underpinning the development of the metabolic syndrome. Hypoxia-induced augmentation of lactate production may also stimulate the “browning” of white fat depots through recruitment of UCP1 and the development of brite adipocytes.

18F-FDG PET/CT monitoring of β3 agonist-stimulated brown adipocyte recruitment in white adipose tissue.

There is rising interest in recruitment of brown adipocytes into white adipose tissue (WAT) as a means to augment energy expenditure for weight reduction. We thus investigated the potential of (18)F-FDG uptake as an imaging biomarker that can monitor the process of WAT browning. C57BL/6 mice were treated daily with the β3 agonist CL316,243 (5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylic acid disodium salt), whereas controls received saline. (18)F-FDG small-animal PET/CT was serially performed at 1 h after CL316,243 injection. After sacrifice, interscapular brown adipose tissue (BAT) and WAT depots were extracted, weighed, and measured for (18)F-FDG uptake. Tissues underwent immunostaining, and UCP1 content was quantified by Western blotting. PET/CT showed low (18)F-FDG uptake in both BAT and inguinal WAT at baseline. BAT uptake was substantially increased by a single stimulation with CL316,243. Uptake in inguinal WAT was only modestly elevated by the first stimulation uptake but gradually increased to BAT level by prolonged stimulation. Ex vivo measurements recapitulated the PET findings, and measured (18)F-FDG uptake in other WAT depots was similar to inguinal WAT. WAT browning by prolonged stimulation was confirmed by a substantial increase in uncoupling protein 1 (UCP1), cytochrome-c oxidase 4 (COX4), and PR domain containing 16 (PRDM16) staining as markers of brown adipocytes. UCP1 content, which served as a measure for extent of browning, was low in baseline inguinal WAT but linearly increased over 10 d of CL316,243 injection. Finally, image-based and ex vivo-measured (18)F-FDG uptake in inguinal WAT correlated well with UCP1 content. (18)F-FDG PET/CT has the capacity to monitor brown adipocyte recruitment into WAT depots in vivo and may thus be useful for screening the efficacy of strategies to promote WAT browning.

Male bovine GH transgenic mice have decreased adiposity with an adipose depot-specific increase in immune cell populations.

White adipose tissue (WAT) is composed of mature adipocytes and a stromal vascular fraction (SVF), which contains a variety of cells, including immune cells that vary among the different WAT depots. Growth hormone (GH) impacts immune function and adiposity in an adipose depot-specific manner. However, its effects on WAT immune cell populations remain unstudied. Bovine GH transgenic (bGH) mice are commonly used to study the in vivo effects of GH. These giant mice have an excess of GH action, impaired glucose metabolism, decreased adiposity, increased lean mass, and a shortened lifespan. Therefore, the purpose of this study was to characterize the WAT depot-specific differences in immune cell populations in the presence of excess GH in vivo. Three WAT depots were assessed: inguinal (sc), epididymal (EPI), and mesenteric (MES). Subcutaneous and MES bGH WAT depots showed a significantly higher number of total SVF cells, yet only MES bGH WAT had higher leukocyte counts compared with control samples. By means of flow cytometry analysis of the SVF, we detected greater macrophage and regulatory T-cell infiltration in sc and MES bGH WAT depots compared with controls. However, no differences were observed in the EPI WAT depot. RNA-sequencing confirmed significant alterations in pathways related to T-cell infiltration and activation in the sc depot with fewer significant changes in the EPI bGH WAT depot. These findings collectively point to a previously unrecognized role for GH in influencing the distribution of WAT immune cell populations in a depot-specific manner.

Notch signaling pathway activation in normal and hyperglycemic rats differs in the stem cells of visceral and subcutaneous adipose tissue.

The precise mechanisms underlying the differential function and cardiometabolic risk of white adipose tissue (WAT) remain unclear. Visceral adipose tissue (VWAT) and subcutaneous adipose tissue (SCWAT) have different metabolic functions that seem to be ascribed to their different intrinsic expansion capacities. Here we have hypothesized that the WAT characteristics are determined by the resident adipose-derived stem cells (ASCs) found in the different WAT depots. Therefore, our objective has been to investigate adipogenesis in anatomically distinct fat depots. ASCs from five different WAT depots were characterized in both healthy lean and diabetic obese rats, showing significant differences in expression of some of genes governing the stemness and the earlier adipogenic differentiation steps. Notch-target genes [Hes (hairy and enhancer of split) and Hey (hairy/enhancer of split related with YRPW motif) families] were upregulated in ASCs derived from visceral depots. Upon adipogenic differentiation, adipocyte cell markers were downregulated in ASCs from VWAT in comparison to ASCs from SCWAT, revealing a lower adipogenic capacity in ASCs of visceral origin than in those of SCWAT in accordance with the differential activation of Notch signaling. Notch upregulation by its activator phenethyl isothiocyanate attenuated the adipogenic differentiation of ASCs from SCWAT whereas Notch inhibition by N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) increased the adipogenic differentiation of ASCs from visceral origin. In conclusion, the differential activation of Notch in ASCs is the origin of the different intrinsic WAT expansion capacities that contribute to the regional variations in WAT homeostasis and to its associated cardiometabolic risk.

Macrophage elastase suppresses white adipose tissue expansion with cigarette smoking.

Macrophage elastase (MMP12) is a key mediator of cigarette smoke (CS)-induced emphysema, yet its role in other smoking related pathologies remains unclear. The weight suppressing effects of smoking are a major hindrance to cessation efforts, and MMP12 is known to suppress the vascularization on which adipose tissue growth depends by catalyzing the formation of antiangiogenic peptides endostatin and angiostatin. The goal of this study was to determine the role of MMP12 in adipose tissue growth and smoking-related suppression of weight gain. Whole body weights and white adipose depots from wild-type and Mmp12-deficient mice were collected during early postnatal development and after chronic CS exposure. Adipose tissue specimens were analyzed for angiogenic and adipocytic markers and for content of the antiangiogenic peptides endostatin and angiostatin. Cultured 3T3-L1 adipocytes were treated with adipose tissue homogenate to examine its effects on vascular endothelial growth factor (VEGF) expression and secretion. MMP12 content and activity were increased in the adipose tissue of wild-type mice at 2 weeks of age, leading to elevated endostatin production, inhibition of VEGF secretion, and decreased adipose tissue vascularity. By 8 weeks of age, adipose MMP12 levels subsided, and the protein was no longer detectable. However, chronic CS exposure led to macrophage accumulation and restored adipose MMP12 activity, thereby suppressing adipose tissue mass and vascularity. Our results reveal a novel systemic role for MMP12 in postnatal adipose tissue expansion and smoking-associated weight loss by suppressing vascularity within the white adipose tissue depots.

Molecular insights into the role of white adipose tissue in metabolically unhealthy normal weight and metabolically healthy obese individuals.

Obesity is a risk factor for the development of type 2 diabetes and cardiovascular disease. However, it is now recognized that a subset of individuals have reduced cardiometabolic risk despite being obese. Paradoxically, a subset of lean individuals is reported to have high risk for cardiometabolic complications. These distinct subgroups of individuals are referred to as metabolically unhealthy normal weight (MUNW) and metabolically healthy obese (MHO). Although the clinical relevance of these subgroups remains debated, evidence shows a critical role for white adipose tissue (WAT) function in the development of these phenotypes. The goal of this review is to provide an overview of our current state of knowledge regarding the molecular and metabolic characteristics of WAT associated with MUNW and MHO. In particular, we discuss the link between different WAT depots, immune cell infiltration, and adipokine production with MUNW and MHO. Furthermore, we also highlight recent molecular insights made with genomic technologies showing that processes such as oxidative phosphorylation, branched-chain amino acid catabolism, and fatty acid β-oxidation differ between these phenotypes. This review provides evidence that WAT function is closely linked with cardiometabolic risk independent of obesity and thus contributes to the development of MUNW and MHO.

Resveratrol attenuates intermittent hypoxia-induced macrophage migration to visceral white adipose tissue and insulin resistance in male mice.

Chronic intermittent hypoxia during sleep (IH), as occurs in sleep apnea, promotes systemic insulin resistance. Resveratrol (Resv) has been reported to ameliorate high-fat diet-induced obesity, inflammation, and insulin resistance. To examine the effect of Resv on IH-induced metabolic dysfunction, male mice were subjected to IH or room air conditions for 8 weeks and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin, and leptin were obtained, homeostatic model assessment of insulin resistance index levels were calculated, and insulin sensitivity tests (phosphorylated AKT [also known as protein kinase B]/total AKT) were performed in 2 visceral white adipose tissue (VWAT) depots (epididymal [Epi] and mesenteric [Mes]) along with flow cytometry assessments for VWAT macrophages and phenotypes (M1 and M2). IH-Veh and IH-Resv mice showed initial reductions in food intake with later recovery, with resultant lower body weights after 8 weeks but with IH-Resv showing better increases in body weight vs IH-Veh. IH-Veh and IH-Resv mice exhibited lower fasting glucose levels, but only IH-Veh had increased homeostatic model assessment of insulin resistance index vs all 3 other groups. Leptin levels were preserved in IH-Veh but were significantly lower in IH-Resv. Reduced VWAT phosphorylated-AKT/AKT responses to insulin emerged in both Mes and Epi in IH-Veh but normalized in IH-Resv. Increases total macrophage counts and in M1 to M2 ratios occurred in IH-Veh Mes and Epi compared all other 3 groups. Thus, Resv ameliorates food intake and weight gain during IH exposures and markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy for metabolic morbidity in the context of sleep apnea.

Heat shock proteins: in vivo heat treatments reveal adipose tissue depot-specific effects.

Heat treatments (HT) and the induction of heat shock proteins (HSPs) improve whole body and skeletal muscle insulin sensitivity while decreasing white adipose tissue (WAT) mass. However, HSPs in WAT have been understudied. The purpose of the present study was to examine patterns of HSP expression in WAT depots, and to examine the effects of a single in vivo HT on WAT metabolism. Male Wistar rats received HT (41°C, 20 min) or sham treatment (37°C), and 24 h later subcutaneous, epididymal, and retroperitoneal WAT depots (SCAT, eWAT, and rpWAT, respectively) were removed for ex vivo experiments and Western blotting. SCAT, eWAT, and rpWAT from a subset of rats were also cultured separately and received a single in vitro HT or sham treatment. HSP72 and HSP25 expression was greatest in more metabolically active WAT depots (i.e., eWAT and rpWAT) compared with the SCAT. Following HT, HSP72 increased in all depots with the greatest induction occurring in the SCAT. In addition, HSP25 increased in the rpWAT and eWAT, while HSP60 increased in the rpWAT only in vivo. Free fatty acid (FFA) release from WAT explants was increased following HT in the rpWAT only, and fatty acid reesterification was decreased in the rpWAT but increased in the SCAT following HT. HT increased insulin responsiveness in eWAT, but not in SCAT or rpWAT. Differences in HSP expression and induction patterns following HT further support the growing body of literature differentiating distinct WAT depots in health and disease.

The "Skinny" on brown fat, obesity, and bone.

The discovery that metabolically active brown fat is present in humans throughout ontogeny raises new questions about the interactions between thermoregulatory, metabolic, and skeletal homeostasis. Brown adipose tissue (BAT) is distinct from white adipose tissue (WAT) for its ability to burn, rather than store, energy. BAT uniquely expresses uncoupling protein-1 (abbreviated as UCP1), which diverts the energy produced by cellular respiration to generate heat. While BAT is found in small mammals, hibernators, and newborns, this depot was thought to regress in humans during early postnatal life. Recent studies revealed that human BAT remains metabolically active throughout childhood and even in adulthood, particularly in response to cold exposure. In addition to the constitutive BAT depots present at birth, BAT cells can be induced within WAT depots under specific metabolic and climatic conditions. These cells, called inducible brown fat, "brite," or beige fat, are currently the focus of intense investigation as a possible treatment for obesity. Inducible brown fat is associated with higher bone mineral density, suggesting that brown fat interacts with bone growth in previously unrecognized ways. Finally, BAT may have contributed to climatic adaptation in hominins. Here, I review current findings on the role of BAT in thermoregulation, bone growth, and metabolism, describe the potential role of BAT in moderating the obesity epidemic, and outline possible functions of BAT across hominin evolutionary history.

A gain-of-function mutation in adenylate cyclase 3 protects mice from diet-induced obesity.

In a screen for genes that affect the metabolic response to high-fat diet (HFD), we selected one line of N-ethyl-N-nitrosourea (ENU)-mutagenized mice, Jll, with dominantly inherited resistance to diet-induced obesity (DIO). Mutant animals had dramatically reduced body weight and fat mass, and low basal insulin and glucose levels relative to unaffected controls. Both white adipose tissue (WAT) and brown adipose tissue (BAT) depots were smaller in mutant animals. Mutant animals fed a HFD gained only slightly more weight than animals fed regular chow, and were protected from hepatic lipid accumulation. The phenotype was genetically linked to a 5.7-Mb interval on chromosome 12, and sequencing of the entire interval identified a single coding mutation, predicted to cause a methionine-to-isoleucine substitution at position 279 of the Adcy3 protein (Adcy3M279I, henceforth referred to as Adcy3Jll). The mutant protein is hyperactive, possibly constitutively so, producing elevated levels of cyclic AMP in a cell-based assay. These mice demonstrate that increased Adcy3 activity robustly protect animals from diet-induced metabolic derangements.

Hepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice

PTEN is a dual lipid/protein phosphatase, downregulated in steatotic livers with obesity or HCV infection. Liver-specific PTEN knockout (LPTEN KO) mice develop steatosis, inflammation/fibrosis and hepatocellular carcinoma with aging, but surprisingly also enhanced glucose tolerance. This study aimed at understanding the mechanisms by which hepatic PTEN deficiency improves glucose tolerance, while promoting fatty liver diseases. Control and LPTEN KO mice underwent glucose/pyruvate tolerance tests and euglycemic-hyperinsulinemic clamps. Body fat distribution was assessed by EchoMRI, CT-scan and dissection analyses. Primary/cultured hepatocytes and insulin-sensitive tissues were analysed ex vivo. PTEN deficiency in hepatocytes led to steatosis through increased fatty acid (FA) uptake and de novo lipogenesis. Although LPTEN KO mice exhibited hepatic steatosis, they displayed increased skeletal muscle insulin sensitivity and glucose uptake, as assessed by euglycemic-hyperinsulinemic clamps. Surprisingly, white adipose tissue (WAT) depots were also drastically reduced. Analyses of key enzymes involved in lipid metabolism further indicated that FA synthesis/esterification was decreased in WAT. In addition, Ucp1 expression and multilocular lipid droplet structures were observed in this tissue, indicating the presence of beige adipocytes. Consistent with a liver to muscle/adipocyte crosstalk, the expression of liver-derived circulating factors, known to impact on muscle insulin sensitivity and WAT homeostasis (e.g. FGF21), was modulated in LPTEN KO mice. Although steatosis develops in LPTEN KO mice, PTEN deficiency in hepatocytes promotes a crosstalk between liver and muscle, as well as adipose tissue, resulting in enhanced insulin sensitivity, improved glucose tolerance and decreased adiposity.

Adaptive thermogenesis in white adipose tissue: is lactate the new brown(ing)?

The prevalence of obesity and type 2 diabetes has become a major economic and medical burden worldwide. Increased food intake and reduced physical activity have contributed to a shift in energy balance, resulting in excess energy storage in the white adipose tissue (WAT) depots. In contrast to WAT, brown adipose tissue (BAT) converts excess energy into heat via uncoupled respiration, which is dependent, in part, on expression by brown adipocytes of the uncoupling protein 1 (UCP1). Thus, an attractive strategy to reduce energy storage is to increase the levels of brown adipocyte activity. Although WAT does not normally express UCP1 or exhibit uncoupled respiration, WAT depots are capable of great plasticity. In response to cold exposure or genetic modifications, mouse white adipocytes can be induced to exhibit brown adipocyte–like character. These cells are known as “brite” (for brown-in-white) or “beige” adipocytes. Factors that are known to increase “browning” in mouse WAT include the transcription factors PGC1α, PRDM16, and members of the PPAR family (1). Additionally, treatment with metabolites, such as bile acids, prostaglandins, and retinoids, promotes the browning of WAT (2). Beige adipocytes express UCP1 and accumulate multilocular lipid droplets similar to genuine brown adipocytes but exhibit a gene expression signature that is distinct from classic brown adipocytes (3,4 …

Adiponectin induces A20 expression in adipose tissue to confer metabolic benefit.

Obesity is a major risk factor for metabolic disease, with white adipose tissue (WAT) inflammation emerging as a key underlying pathology. We detail that mice lacking Reverbα exhibit enhanced fat storage without the predicted increased WAT inflammation or loss of insulin sensitivity. In contrast to most animal models of obesity and obese human patients, Reverbα(-/-) mice exhibit elevated serum adiponectin levels and increased adiponectin secretion from WAT explants in vitro, highlighting a potential anti-inflammatory role of this adipokine in hypertrophic WAT. Indeed, adiponectin was found to suppress primary macrophage responses to lipopolysaccharide and proinflammatory fatty acids, and this suppression depended on glycogen synthase kinase 3β activation and induction of A20. Attenuated inflammatory responses in Reverbα(-/-) WAT depots were associated with tonic elevation of A20 protein and ex vivo shown to depend on A20. We also demonstrate that adipose A20 expression in obese human subjects exhibits a negative correlation with measures of insulin sensitivity. Furthermore, bariatric surgery-induced weight loss was accompanied by enhanced WAT A20 expression, which is positively correlated with increased serum adiponectin and improved metabolic and inflammatory markers, including C-reactive protein. The findings identify A20 as a mediator of adiponectin anti-inflammatory action in WAT and a potential target for mitigating obesity-related pathology.

Grape seed procyanidin supplementation to rats fed a high-fat diet during pregnancy and lactation increases the body fat content and modulates the inflammatory response and the adipose tissue metabolism of the male offspring in youth.

Procyanidins are polyphenolic bioactive compounds that exert beneficial effects against obesity and its related diseases. The aim of this study was to evaluate whether supplementation with low doses of a grape seed procyanidin extract (GSPE) to rats during pre- and postnatal periods provides biological effects to their offspring in youth. The metabolic programming effect of GSPE was evaluated in the 30-day-old male offspring of four groups of rats that were fed either a standard diet (STD) or a high-fat diet (HFD) and that were supplemented with either GSPE (25 mg kg(-1) of body weight per day) or vehicle during pregnancy and lactation. Significant increases in the adiposity index and in the weights of all the white adipose tissue depots studied (retroperitoneal, mesenteric, epididymal (EWAT) and inguinal) were observed in the offspring of rats that were fed a HFD and that were treated with GSPE (HFD-GSPE group) compared with the offspring of rats that were fed the same diet but that did not receive the procyanidins (HFD group). The HFD-GSPE animals also exhibited a higher number of cells in the EWAT, a sharp decrease in the circulating levels of monocyte chemoattractant protein-1 (MCP-1) and a moderate decrease in the plasma glycerol levels. The transcriptomic analysis performed in the EWAT showed 238 genes that were differentially expressed between the HFD and the HFD-GSPE animals, most of which were associated with the immune function and the inflammatory response, in addition to genes associated with adipose tissue remodeling and function, lipid and glucose homeostasis and the metabolism of methyl groups. The GSPE treatment in rats that were fed an HFD during pregnancy and lactation induced a clear metabolic programming effect in the offspring, increasing adiposity, decreasing the circulating levels of MCP-1 and changing the gene expression in the EWAT toward a better inflammatory profile.

The lipid profile of brown adipose tissue is sex-specific in mice

Brown adipose tissue (BAT) is a thermogenic organ with a vital function in small mammals and potential as metabolic drug target in humans. By using high-resolution LC-tandem-mass spectrometry, we quantified 329 lipid species from 17 (sub)classes and identified the fatty acid composition of all phospholipids from BAT and subcutaneous and gonadal white adipose tissue (WAT) from female and male mice. Phospholipids and free fatty acids were higher in BAT, while DAG and TAG levels were higher in WAT. A set of phospholipids dominated by the residue docosahexaenoic acid, which influences membrane fluidity, showed the highest specificity for BAT. We additionally detected major sex-specific differences between the BAT lipid profiles, while samples from the different WAT depots were comparatively similar. Female BAT contained less triacylglycerol and more phospholipids rich in arachidonic and stearic acid whereas another set of fatty acid residues that included linoleic and palmitic acid prevailed in males. These differences in phospholipid fatty acid composition could greatly affect mitochondrial membranes and other cellular organelles and thereby regulate the function of BAT in a sex-specific manner.