Brown and white adipose tissues: intrinsic differences in gene expression and response to cold exposure in mice.

Brown adipocytes dissipate energy, whereas white adipocytes are an energy storage site. We explored the plasticity of different white adipose tissue depots in acquiring a brown phenotype by cold exposure. By comparing cold-induced genes in white fat to those enriched in brown compared with white fat, at thermoneutrality we defined a "brite" transcription signature. We identified the genes, pathways, and promoter regulatory motifs associated with "browning," as these represent novel targets for understanding this process. For example, neuregulin 4 was more highly expressed in brown adipose tissue and upregulated in white fat upon cold exposure, and cell studies showed that it is a neurite outgrowth-promoting adipokine, indicative of a role in increasing adipose tissue innervation in response to cold. A cell culture system that allows us to reproduce the differential properties of the discrete adipose depots was developed to study depot-specific differences at an in vitro level. The key transcriptional events underpinning white adipose tissue to brown transition are important, as they represent an attractive proposition to overcome the detrimental effects associated with metabolic disorders, including obesity and type 2 diabetes.

Chronic intermittent hypoxia triggers cardiac fibrosis: Role of epididymal white adipose tissue senescent remodeling?

AIM: Obstructive sleep apnea (OSA) is a growing health problem affecting nearly 1 billion people worldwide. The landmark feature of OSA is chronic intermittent hypoxia (CIH), accounting for multiple organ damage, including heart disease. CIH profoundly alters both visceral white adipose tissue (WAT) and heart structure and function, but little is known regarding inter-organ interaction in the context of CIH. We recently showed that visceral WAT senescence drives myocardial alterations in aged mice without CIH. Here, we aimed at investigating whether CIH induces a premature visceral WAT senescent phenotype, triggering subsequent cardiac remodeling. METHODS: In a first experiment, 10-week-old C57bl6J male mice (n = 10/group) were exposed to 14 days of CIH (8 h daily, 5%-21% cyclic inspired oxygen fraction, 60 s per cycle). In a second series, mice were submitted to either epididymal WAT surgical lipectomy or sham surgery before CIH exposure. Finally, we used p53 deficient mice or Wild-type (WT) littermates, also exposed to the same CIH protocol. Epididymal WAT was assessed for fibrosis, DNA damages, oxidative stress, markers of senescence (p16, p21, and p53), and inflammation by RT-qPCR and histology, and myocardium was assessed for fibrosis and cardiomyocyte hypertrophy. RESULTS: CIH-induced epididymal WAT remodeling characterized by increased fibrosis, oxidative stress, DNA damage response, inflammation, and increased expression of senescent markers. CIH-induced epididymal WAT remodeling was associated with subtle and early myocardial interstitial fibrosis. Both epididymal WAT surgical lipectomy and p53 deletion prevented CIH-induced myocardial fibrosis. CONCLUSION: Short-term exposure to CIH induces epididymal WAT senescent remodeling and cardiac interstitial fibrosis, the latter being prevented by lipectomy. This finding strongly suggests visceral WAT senescence as a new target to mitigate OSA-related cardiac disorders.

Blockade of TGF-ß signalling alleviates human adipose stem cell senescence induced by native ECM in obesity visceral white adipose tissue.

BACKGROUND: Abdominal obesity is appreciated as a major player in insulin resistance and metabolically dysfunctional adipose tissue. Inappropriate extracellular matrix (ECM) remodelling and functional alterations in human adipose stromal/stem cells (hASCs) have been linked with visceral white adipose tissue (vWAT) dysfunction in obesity. Understanding the interactions between hASCs and the native ECM environment in obese vWAT is required for the development of future therapeutic approaches for obesity-associated metabolic complications. METHODS: The phenotypes and transcriptome properties of hASCs from the vWAT of obese patients and lean donors were assessed. The hASC-derived matrix from vWAT of obese or lean patients was generated in vitro using a decellularized method. The topography and the major components of the hASC-derived matrix were determined. The effects of the obese hASC-derived matrix on cell senescence and mitochondrial function were further determined. RESULTS: We showed that hASCs derived from the vWAT of obese patients exhibited senescence and were accompanied by the increased production of ECM. The matrix secreted by obese hASCs formed a fibrillar suprastructure with an abundance of fibronectin, type I collagen, and transforming growth factor beta 1 (TGF-ß1), which resembles the native matrix microenvironment of hASCs in vWAT derived from obese patients. Furthermore, the obese hASC-derived matrix promoted lean hASC ageing and induced mitochondrial dysfunction compared to the lean hASC-derived matrix. Blockade of TGF-ß1 signalling using an anti-TGF-ß1 neutralizing antibody alleviated the lean hASC senescence and mitochondrial dysfunction induced by the obese hASC-derived matrix. CONCLUSIONS: Native ECM in obesity vWAT initiates hASC senescence through TGF-ß1-mediated mitochondrial dysfunction. These data provide a key mechanism for understanding the importance of cell-ECM interactions in hASCs senescence in obesity.

Dietary n-3 and n-6 polyunsaturated fatty acids differentially modulate the adiponectin and leptinmediated major signaling pathways in visceral and subcutaneous white adipose tissue in high fat diet induced obesity in Wistar rats.

Obesity is a chronic metabolic disease that involves excessive accumulation of fat in white adipose tissue (WAT). Apart from storing excess fats, WAT also serves as an important endocrine organ secreting adipocytokines such as adiponectin and leptin. Adiponectin and leptin bind to their transmembrane receptors adiponectin receptor 1 (AdipoR1)/adiponectin receptor 2 (AdipoR2) and Ob-R, respectively, and mediate their effect on metabolism by regulating multiple downstream targets. Dietary fat is considered the main culprit behind obesity development. Numerous preclinical studies have highlighted role of essential polyunsaturated fatty acids (PUFAs), particularly n-3 PUFAs, in prevention of obesity. Despite emerging data, there still is no clear understanding of the mechanism of action of n-3 PUFAs and n-6 PUFAs on adipose tissue function in two functionally and anatomically different depots of WAT: visceral and subcutaneous. We designed this study using a high fat diet (HFD) fed rodent model of obesity to test our hypothesis that n-3 and n-6 PUFAs possibly differentially modulate adipokine secretion and downstream metabolic pathways such as peroxisome proliferator-activated receptor-γ (PPAR-γ), protein kinase B (AKT)-forkhead box O1 (FOXO1), and Janus kinase-signal transducer and activator of transcription in obesity. The results of the current study showed that n-3 PUFAs upregulate the expression of AdipoR1/R2 and ameliorate the effects of HFD by modulating adipogenesis via PPAR-γ and by improving glucose tolerance and lipid metabolism via AKT-FOXO1 axis in fish oil fed rats. However, n-6 PUFAs did not show any remarkable change compared with HFD fed animals. Our study highlights that n-3 PUFAs modulate expression of various targets in adiponectin and leptin signaling cascade, bringing about an overall reduction in obesity and improvement in adipose tissue function in HFD induced obesity.

Exercise Equals the Mobilization of Visceral versus Subcutaneous Adipose Fatty Acid Molecules in Fasted Rats Associated with the Modulation of the AMPK/ATGL/HSL Axis.

Combining exercise with fasting is known to boost fat mass-loss, but detailed analysis on the consequential mobilization of visceral and subcutaneous WAT-derived fatty acids has not been performed. In this study, a subset of fasted male rats (66 h) was submitted to daily bouts of mild exercise. Subsequently, by using gas chromatography-flame ionization detection, the content of 22 fatty acids (FA) in visceral (v) versus subcutaneous (sc) white adipose tissue (WAT) depots was compared to those found in response to the separate events. Findings were related to those obtained in serum and liver samples, the latter taking up FA to increase gluconeogenesis and ketogenesis. Each separate intervention reduced scWAT FA content, associated with increased levels of adipose triglyceride lipase (ATGL) protein despite unaltered AMP-activated protein kinase (AMPK) Thr172 phosphorylation, known to induce ATGL expression. The mobility of FAs from vWAT during fasting was absent with the exception of the MUFA 16:1 n-7 and only induced by combining fasting with exercise which was accompanied with reduced hormone sensitive lipase (HSL) Ser563 and increased Ser565 phosphorylation, whereas ATGL protein levels were elevated during fasting in association with the persistently increased phosphorylation of AMPK at Thr172 both during fasting and in response to the combined intervention. As expected, liver FA content increased during fasting, and was not further affected by exercise, despite additional FA release from vWAT in this condition, underlining increased hepatic FA metabolism. Both fasting and its combination with exercise showed preferential hepatic metabolism of the prominent saturated FAs C:16 and C:18 compared to the unsaturated FAs 18:1 n-9 and 18:2 n-6:1. In conclusion, depot-specific differences in WAT fatty acid molecule release during fasting, irrelevant to their degree of saturation or chain length, are mitigated when combined with exercise, to provide fuel to surrounding organs such as the liver which is correlated with increased ATGL/ HSL ratios, involving AMPK only in vWAT.

Bidirectional communication between brain and visceral white adipose tissue: Its potential impact on Alzheimer's disease.

A variety of axes between brain and abdominal organs have been reported, but the interaction between brain and visceral white adipose tissue (vWAT) remains unclear. In this review, we summarized human studies on the association between brain and vWAT, and generalized their interaction and the underlying mechanisms according to animal and cell experiments. On that basis, we come up with the concept of the brain-vWAT axis (BVA). Furthermore, we analyzed the potential mechanisms of involvement of BVA in the pathogenesis of Alzheimer's disease (AD), including vWAT-derived fatty acids, immunological properties of vWAT, vWAT-derived retinoic acid and vWAT-regulated insulin resistance. The proposal of BVA may expand our understanding to some extent of how the vWAT impacts on brain health and diseases, and provide a novel approach to study the pathogenesis and treatment strategies of neurodegenerative disorders.

The effect of trimethylamine N-oxide on the metabolism of visceral white adipose tissue in spontaneously hypertensive rat.

Strong links have been reported among trimethylamine N-oxide (TMAO), visceral white adipose tissue (vWAT), and cardiometabolic diseases. However, the effects of TMAO on vWAT in hypertension remained incompletely explored. The impact of a chronic 22-week-long treatment with 1 g/L TMAO on vWAT, and its transcriptional and metabolic changes in spontaneously hypertensive rats (SHRs) were evaluated by serum cytokine measurements, histological analysis, fatty acid determinations, and co-expression network analyses. TMAO increased the serum interleukin-6 levels and insulin secretion in SHRs. The adipocyte size was diminished in the SHR 1 g/L TMAO group. In addition, one kind of monounsaturated fatty acids (cis-15-tetracosenoate) and four kinds of polyunsaturated fatty acids (cis-11,14,17-eicosatrienoic acid, docosatetraenoate, docosapentaenoate n-3, and docosapentaenoate n-6) were elevated by TMAO treatment. Three co-expression modules significantly related to TMAO treatment were identified and pathway enrichment analyses indicated that phagosome, lysosome, fatty acid metabolism, valine, leucine, and isoleucine degradation and metabolic pathways were the most significantly altered biological pathways. This study shed new light on the metabolic roles of TMAO on the vWAT of SHRs. TMAO regulated the metabolic status of vWAT, including reduced lipogenesis and an improved specific fatty acid composition. The mechanisms underlying these effects likely involve phagosome and lysosome pathways.

3,5-Diiodo-L-Thyronine (T2) Administration Affects Visceral Adipose Tissue Inflammatory State in Rats Receiving Long-Lasting High-Fat Diet.

3,5-diiodo-thyronine (T2), an endogenous metabolite of thyroid hormones, exerts beneficial metabolic effects. When administered to overweight rats receiving a high fat diet (HFD), it significantly reduces body fat accumulation, which is a risk factor for the development of an inflammatory state and of related metabolic diseases. In the present study, we focused our attention on T2 actions aimed at improving the adverse effects of long-lasting HFD such as the adipocyte inflammatory response. For this purpose, three groups of rats were used throughout: i) receiving a standard diet for 14 weeks; ii) receiving a HFD for 14 weeks, and iii) receiving a HFD for 14 weeks with a simultaneous daily injection of T2 for the last 4 weeks. The results showed that T2 administration ameliorated the expression profiles of pro- and anti-inflammatory cytokines, reduced macrophage infiltration in white adipose tissue, influenced their polarization and reduced lymphocytes recruitment. Moreover, T2 improved the expression of hypoxia markers, all altered in HFD rats, and reduced angiogenesis by decreasing the pro-angiogenic miR126 expression. Additionally, T2 reduced the oxidative damage of DNA, known to be associated to the inflammatory status. This study demonstrates that T2 is able to counteract some adverse effects caused by a long-lasting HFD and to produce beneficial effects on inflammation. Irisin and SIRT1 pathway may represent a mechanism underlying the above described effects.

Gestational sleep apnea perturbations induce metabolic disorders by divergent epigenomic regulation.

Aim: Late-gestational sleep fragmentation (LG-SF) and intermittent hypoxia (LG-IH), two hallmarks of obstructive sleep apnea, lead to metabolic dysfunction in the offspring. We investigated specific biological processes that are epigenetically regulated by LG-SF and LG-IH. Materials & methods: We analyzed DNA methylation profiles in offspring visceral white adipose tissues by MeDIP-chip followed by pathway analysis. Results: We detected 1187 differentially methylated loci (p < 0.01) between LG-SF and LG-IH. Epigenetically regulated genes in LG-SF offspring were associated with lipid and glucose metabolism, whereas those in LG-IH were related to inflammatory signaling and cell proliferation. Conclusion: While LG-SF and LG-IH will result in equivalent phenotypic alterations in offspring, each paradigm appears to operate through epigenetic regulation of different biological processes.

AdipoAtlas: A reference lipidome for human white adipose tissue.

Obesity, characterized by expansion and metabolic dysregulation of white adipose tissue (WAT), has reached pandemic proportions and acts as a primer for a wide range of metabolic disorders. Remodeling of WAT lipidome in obesity and associated comorbidities can explain disease etiology and provide valuable diagnostic and prognostic markers. To support understanding of WAT lipidome remodeling at the molecular level, we provide in-depth lipidomics profiling of human subcutaneous and visceral WAT of lean and obese individuals. We generate a human WAT reference lipidome by performing tissue-tailored preanalytical and analytical workflows, which allow accurate identification and semi-absolute quantification of 1,636 and 737 lipid molecular species, respectively. Deep lipidomic profiling allows identification of main lipid (sub)classes undergoing depot-/phenotype-specific remodeling. Previously unanticipated diversity of WAT ceramides is now uncovered. AdipoAtlas reference lipidome serves as a data-rich resource for the development of WAT-specific high-throughput methods and as a scaffold for systems medicine data integration.

Adipose tissue of female Wistar rats respond to Ilex paraguariensis treatment after ovariectomy surgery.

BACKGROUND AND AIM: Metabolic disturbances are known for their increasing epidemiological importance. Ilex paraguariensis presents a potential option for mitigating lipid metabolism imbalance. However, most of the literature to date has not considered sex bias. This study aimed to evaluate the effect of Ilex paraguariensis on the metabolism of different adipose tissue depots in males and females. EXPERIMENTAL PROCEDURE: After ovariectomy, female Wistar rats received daily treatment with the extract (1 g/kg) for forty-five days. Biochemical serum parameters and tissue metabolism were evaluated. Oxidation, lipogenesis and lipolysis were evaluated in brown, white visceral, retroperitoneal and gonadal adipose tissues. RESULTS AND CONCLUSION: The results showed that treatment with the extract led to a reduced weight gain in ovariectomised females in comparison to control. The triglyceride concentration was decreased in males. Glucose oxidation and lipid synthesis in visceral and retroperitoneal adipose tissues were restored in ovariectomised females after treatment. The response to epinephrine decreased in visceral adipose tissue of control males; however, lipolysis in females did not respond to ovariectomy or treatment. These findings highlight the enormous potential effects of I. paraguariensis on lipid metabolism, modulating lipogenic pathways in females and lipolytic pathways in males. Furthermore, the sex approach applied in this study contributes to more effective screening of the effects of I. paraguariensis bioactive substances.

Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease.

Adipose tissue plays essential roles in maintaining lipid and glucose homeostasis. To date several types of adipose tissue have been identified, namely white, brown, and beige, that reside in various specific anatomical locations throughout the body. The cellular composition, secretome, and location of these adipose depots define their function in health and metabolic disease. In obesity, adipose tissue becomes dysfunctional, promoting a pro-inflammatory, hyperlipidemic and insulin resistant environment that contributes to type 2 diabetes mellitus (T2DM). Concurrently, similar features that result from adipose tissue dysfunction also promote cardiovascular disease (CVD) by mechanisms that can be augmented by T2DM. The mechanisms by which dysfunctional adipose tissue simultaneously promote T2DM and CVD, focusing on adipose tissue depot-specific adipokines, inflammatory profiles, and metabolism, will be the focus of this review. The impact that various T2DM and CVD treatment strategies have on adipose tissue function and body weight also will be discussed.

Effects of irisin on the differentiation and browning of human visceral white adipocytes.

BACKGROUND: The aim of this study was to explore the effects of irisin on human visceral adipose tissue and adipocytes functions. METHODS: Fresh human visceral white adipose tissues derived from 11 donors were used to examine the effects of irisin on browning, adipogenesis and osteogenesis gene expression, and anti-inflammatory properties. Preadipocytes were also used to examine the effects of irisin on mitochondrial respiration, adipogenic differentiation, and osteogenic differentiation. KEY RESULTS: Irisin significantly increased cellular mitochondrial energy metabolism in differentiated visceral adipocytes. Irisin also increased mRNA levels of transcriptional regulators of brite/beige adipocytes (UCP-1, PGC1α, PRDM16, TMEM26, and CD137) in subcutaneous white adipose tissue but not in visceral/brown adipose tissue or their derived mature adipocytes. In parallel, irisin increased the protein levels of UCP-1 in subcutaneous white adipose tissue, but had no effect on the expression of this protein in visceral white adipose tissue and perirenal brown adipose tissue. However, irisin inhibited adipogenic differentiation, promoted osteogenic differentiation in visceral adipocytes, down-regulated adipogenesis, and upregulated osteogenesis genes expression in visceral fat tissue. Moreover, administration of irisin reduced the expression of proinflammatory marker mRNAs in both visceral and subcutaneous white adipose tissue. CONCLUSIONS: Our data suggest that (1) irisin may increase mitochondrial respiration and glycolysis in visceral adipocytes by a UCP-1 independent pathway; (2) irisin promotes anti-inflammatory activity on fat tissue.

3,5-Diiodo-L-Thyronine Exerts Metabolically Favorable Effects on Visceral Adipose Tissue of Rats Receiving a High-Fat Diet.

When administered to rats receiving a high-fat diet (HFD), 3,5-diiodo-L-thyronine (3,5-T2) [at a dose of 25 µg/100 g body weight (BW)] is known to increase energy expenditure and to prevent HFD-induced adiposity. Here, we investigated which cellular and molecular processes in visceral white adipose tissue (VAT) contributed to the beneficial effect of 3,5-T2 over time (between 1 day and 4 weeks following administration). 3,5-T2 programmed the adipocyte for lipolysis by rapidly inducing hormone sensitive lipase (HSL) phosphorylation at the protein kinase A-responsive site Ser563, accompanied with glycerol release at the 1-week time-point, contributing to the partial normalization of adipocyte volume with respect to control (N) animals. After two weeks, when the adipocyte volumes of HFD-3,5-T2 rats were completely normalized to those of the controls (N), 3,5-T2 consistently induced HSL phosphorylation at Ser563, indicative of a combined effect of 3,5-T2-induced adipose lipolysis and increasing non-adipose oxidative metabolism. VAT proteome analysis after 4 weeks of treatment revealed that 3,5-T2 significantly altered the proteomic profile of HFD rats and produced a marked pro-angiogenic action. This was associated with a reduced representation of proteins involved in lipid storage or related to response to oxidative stress, and a normalization of the levels of those involved in lipogenesis-associated mitochondrial function. In conclusion, the prevention of VAT mass-gain by 3,5-T2 occurred through different molecular pathways that, together with the previously reported stimulation of resting metabolism and liver fatty acid oxidation, are associated with an anti adipogenic/lipogenic potential and positively impact on tissue health.

La insuficiencia cardíaca crónica propicia la aparición de diabetes mellitus tipo 2 / Chronic heart failure fosters the onset of type 2 diabetes mellitus

Resumen La insuficiencia cardíaca crónica (IC) propicia la aparición de diabetes mellitus tipo 2 (DM2) y este hecho es poco conocido y entendido. El propósito de este artículo es revisar los mecanismos que se activan en la IC para inducir la aparición de la diabetes mellitus 2, sus implicaciones cardio-metabólicas y los factores de riesgo identificados, como aporte necesario a la escasa información disponible en publicaciones médicas. La resistencia a la insulina, la inflamación, el estrés oxidativo y la vasoconstricción sistémica están directamente orquestadas desde el corazón en IC. El tratamiento actual de la insuficiencia cardíaca con fracción de eyección ventricular izquierda reducida (FEVIr) fundamentado en inhibidores del cotransportador sodio glucosa tipo 2 (iSGTL2), beta-bloqueadores, inhibidor del receptor de angiotensina/neprilisina (IRAN)/IECA/ARA II y antagonistas del receptor mineralocorticoide, podría tener implicaciones favorables para evitar el desarrollo de diabetes mellitus en pacientes con insuficiencia cardíaca crónica, aunque no hay aún respaldo suficiente en la evidencia disponible, quizá por la falta de reconocimiento del problema expuesto.

Abstract Chronic heart failure (HF) fosters the onset of type 2 diabetes mellitus, and this is a little known and understood fact. The purpose of this article is to review the mechanisms that are activated in HF to induce the onset of type 2 diabetes mellitus, its cardio-metabolic implications, and the identified risk factors, as a necessary contribution to the scant available information in medical publications. Insulin resistance, inflammation, oxidative stress and systemic vasoconstriction are directly orchestrated by the heart in HF. The current treatment for heart failure with reduced ejection fraction (HFrEF), based on sodium-glucose transport protein 2 (SGLT2) inhibitors, angiotensin receptor-neprilysin inhibitors (ARNIs)/ACE inhibitors/ARBs and mineralocorticoid receptor antagonists, could have beneficial effects for preventing the onset of diabetes mellitus in patients with chronic HF, although the available evidence does not yet provide sufficient support, perhaps due to a lack of recognition of this problem.

Metabolic Response of Visceral White Adipose Tissue of Obese Mice Exposed for 5 Days to Human Room Temperature Compared to Mouse Thermoneutrality.

Housing of laboratory mice at room temperature (22°C) might be considered a constant cold stress, which induces a thermogenic program in brown adipose tissue (BAT). However, the early adaptive response of white adipose tissue (WAT), the fat storage organ of the body, to a change from thermoneutrality to room temperature is not known. This was investigated here for various WAT depots, focusing on epididymal WAT (eWAT), widely used as reference depot. Male adult diet-induced obese (DIO) C57BL/6JOlaHsd mice housed at thermoneutrality (29°C), were for 5 days either switched to room temperature (22°C) or remained at thermoneutrality. Energy metabolism was continuously measured using indirect calorimetry. At the end of the study, serum metabolomics and WAT transcriptomics were performed. We confirmed activation of the thermogenic program in 22°C housed mice. Body weight and total fat mass were reduced. Whole body energy expenditure (EE) was increased, with a higher fatty acid to carbohydrate oxidation ratio and increased serum acylcarnitine levels, while energy intake was not significantly different between the two groups. Transcriptome analysis of eWAT identified tissue remodeling and inflammation as the most affected processes. Expression of pro-inflammatory M1 macrophage-related genes, and M1 over M2 macrophage ratio were decreased, which might be linked to an increased insulin sensitivity. Markers of thermogenesis were not altered in eWAT. Decreased expression of tryptophan hydroxylase 2 (Tph2) and cholecystokinin (Cck) might represent altered neuroendocrine signaling. eWAT itself does not show increased fatty acid oxidation. The three measured WATs, epididymal, mesenteric, and retroperitoneal, showed mainly similar responses; reduced inflammation (s100a8), decreased carbohydrate oxidation, and no or small differences in fatty acid oxidation. However, Ucp1 was only expressed and increased in rWAT in 22°C housed mice. Cck expression was decreased in the three WATs, significantly in eWAT and rWAT, in contrast to Tph2, which was decreased in eWAT while not expressed in mWAT and rWAT. Our data show that tissue remodeling, inflammation and neuroendocrine signaling are early responses in WAT to a moderate decrease in environmental temperature.

From chronic overnutrition to metaflammation and insulin resistance: adipose tissue and liver contributions.

The close association of obesity with an increased risk of metabolic diseases, such as insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease, is now well established. In this review, we aim first to describe the inflammatory process activated in response to overnutrition, especially in the liver and the adipose tissue. We then discuss the systemic effects of low-grade inflammation on the onset of insulin resistance. Particular attention is given to a series of very recent reports that identify not only processes but also molecules (lipids and metabolites) that interfere with the normal insulin signaling. Finally, special notes concerning the roles of peroxisome proliferator-activated receptors in the various processes will be made.

Wt1, the mesothelium and the origins and heterogeneity of visceral fat progenitors.

One major gap in adipocyte biology has been a lack of understanding of the developmental origins of the different visceral white adipose tissue (WAT) depots and subcutaneous WAT. In a recent study we showed that most visceral WAT but no subcutaneous WAT arises from cells expressing the Wilms' tumor 1 (Wt1) gene late in mouse gestation.(1) Wt1 continues to be expressed in visceral WAT progenitors into adult life. We also showed that visceral WAT is lined by a mesothelium and provided evidence that this structure is the source of adipocytes. Our study also adds to the growing body of evidence that there is heterogeneity in the visceral progenitors, such that there are Wt1-expressing and non-expressing subsets, the relative proportions of which vary between depots. This raises the enticing prospect that the adipocytes arising from these progenitor subsets may have different properties and our preliminary data support this notion. Finally, evidence from our study and one from Spiegelman's group(2) suggests that Wt1 is not just a marker but regulates visceral WAT identity and the progenitor population. We discuss the implications of this work and some of the questions and future directions that arise from it.

Control of adipocyte differentiation in different fat depots; implications for pathophysiology or therapy.

Adipocyte differentiation and its impact on restriction or expansion of particular adipose tissue depots have physiological and pathophysiological significance in view of the different functions of these depots. Brown or "beige" fat [brown adipose tissue (BAT)] expansion can enhance thermogenesis, lipid oxidation, insulin sensitivity, and glucose tolerance; conversely expanded visceral fat [visceral white adipose tissue (VAT)] is associated with insulin resistance, low grade inflammation, dyslipidemia, and cardiometabolic risk. The largest depot, subcutaneous white fat [subcutaneous white adipose tissue (SAT)], has important beneficial characteristics including storage of lipid "out of harms way" and secretion of adipokines, especially leptin and adiponectin, with positive metabolic effects including lipid oxidation, energy utilization, enhanced insulin action, and an anti-inflammatory role. The absence of these functions in lipodystrophies leads to major metabolic disturbances. An ability to expand white adipose tissue adipocyte differentiation would seem an important defense mechanism against the detrimental effects of energy excess and limit harmful accumulation of lipid in "ectopic" sites, such as liver and muscle. Adipocyte differentiation involves a transcriptional cascade with PPARγ being most important in SAT but less so in VAT, with increased angiogenesis also critical. The transcription factor, Islet1, is fairly specific to VAT and in vitro inhibits adipocyte differentiation. The physiological importance of Islet1 requires further study. Basic control of differentiation is similar in BAT but important differences include the effect of PGC-1α on mitochondrial biosynthesis and upregulation of UCP1; also PRDM16 plays a pivotal role in expression of the BAT phenotype. Modulation of the capacity or function of these different adipose tissue depots, by altering adipocyte differentiation or other means, holds promise for interventions that can be helpful in human disease, particularly cardiometabolic disorders associated with the world wide explosion of obesity.

M1-M2 balancing act in white adipose tissue browning - a new role for RIP140.

A "Holy Grail" sought in medical treatment of obesity is to be able to biologically reprogram their adipose tissues to burn fat rather than store it. White adipose tissue (WAT) stores fuel and its expansion underlines insulin resistance (IR) whereas brown adipose tissue (BAT) burns fuel and stimulates insulin sensitivity. These two types of fats seesaw within our bodies via a regulatory mechanism that involves intricate communication between adipocytes and blood cells, particularly macrophages that migrate into adipose deposits. The coregulator, Receptor Interacting Protein 140 (RIP140), plays a key role in regulating this communication. In mice on a high-fat diet, the level of RIP140 in macrophages is dramatically elevated to activate their inflammatory M1 polarization and enhance their recruitment into WAT, facilitating IR. Conversely, lowering the level of RIP140 in macrophages not only reduces M1 macrophages but also expands alternatively polarized, anti-inflammatory M2 macrophages, triggering white adipose tissue browning, fat burning, and restoration of insulin sensitivity. This suggests a potential therapeutic strategy for reversing IR, obesity, and atherosclerotic or even cosmetic fat deposits: therapeutic browning of white adipose deposits by diminishing RIP140 levels in macrophages.