Adipocytes are embedded in a unique extracellular matrix whose main function is to provide mechanical support, in addition to participating in a variety of signaling events. During adipose tissue expansion, the extracellular matrix requires remodeling to accommodate adipocyte growth. Here, we demonstrate a general upregulation of several extracellular matrix components in adipose tissue in the diabetic state, therefore implicating "adipose tissue fibrosis" as a hallmark of metabolically challenged adipocytes. Collagen VI is a highly enriched extracellular matrix component of adipose tissue. The absence of collagen VI results in the uninhibited expansion of individual adipocytes and is paradoxically associated with substantial improvements in whole-body energy homeostasis, both with high-fat diet exposure and in the ob/ob background. Collectively, our data suggest that weakening the extracellular scaffold of adipocytes enables their stress-free expansion during states of positive energy balance, which is consequently associated with an improved inflammatory profile. Therefore, the disproportionate accumulation of extracellular matrix components in adipose tissue may not be merely an epiphenomenon of metabolically challenging conditions but may also directly contribute to a failure to expand adipose tissue mass during states of excess caloric intake.Adipose tissue is a key regulator of systemic energy homeostasis. The physiological state of adipose tissue is driven by cell-autonomous processes within the adipocyte. In addition to this, the adipocyte itself is subject to major modifications by other cell types that infiltrate adipose tissue, such as macrophages and vascular cells; moreover, adipocytes can be markedly influenced by several hormones and cytokines that circulate systemically.Although all these cellular interactions have been the subject of extensive studies in numerous laboratories, the extracellular matrix of adipose tissue has received limited attention to date, despite evidence suggesting that it is a functionally relevant constituent of adipose tissue physiology.It is currently unknown what consequential effects metabolic stress exerts on the extracellular matrix and vice versa. In other words, what is the impact of dysregulation of the extracellular constituents of adipose tissue on the systemic metabolic state?Here, we approach this subject from two different perspectives. We first assessed the overall level of extracellular matrix components under different metabolic conditions and established that the extracellular constituents are globally upregulated during metabolically challenging conditions. We then selected a specific member of the collagen family, collagen VI (exhibiting predominant expression in adipose tissue), and utilized a genetic model of collagen VI disruption to investigate the effects of disruption of the extracellular matrix of adipose tissue. Remarkably, our studies demonstrated that such weakening of adipose tissue extracellular matrix results in considerable improvement of ...

The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. To date, no unifying mechanism explains how adiponectin can exert such a variety of beneficial systemic effects. Here, we show that adiponectin potently stimulates a ceramidase activity associated with its two receptors, adipoR1 and adipoR2, and enhances ceramide catabolism and formation of its anti-apoptotic metabolite – sphingosine-1-phosphate (S1P), independently of AMPK. Using models of inducible apoptosis in pancreatic β-cells and cardiomyocytes, we show that transgenic overproduction of adiponectin decreases caspase-8 mediated death, while genetic adiponectin ablation enhances apoptosis in vivo through a sphingolipid-mediated pathway. Ceramidase activity is impaired in cells lacking both adiponectin receptor isoforms, leading to elevated ceramide levels and enhanced susceptibility to palmitate-induced cell death. Combined, our observations suggest a novel unifying mechanism of action for the beneficial systemic effects exerted by adiponectin, with sphingolipid metabolism as its core upstream component.

Adipose tissue can undergo rapid expansion during times of excess caloric intake. Like a rapidly expanding tumor mass, obese adipose tissue becomes hypoxic due to the inability of the vasculature to keep pace with tissue growth. Consequently, during the early stages of obesity, hypoxic conditions cause an increase in the level of hypoxia-inducible factor 1␣ (HIF1␣) expression. Using a transgenic model of overexpression of a constitutively active form of HIF1␣, we determined that HIF1␣ fails to induce the expected proangiogenic response. In contrast, we observed that HIF1␣ initiates adipose tissue fibrosis, with an associated increase in local inflammation. The dramatic rise in the prevalence of obesity has lead to increased efforts aimed at gaining a better understanding of the physiology and pathophysiology of adipose tissue and adipocytes. One of the more-surprising features of adipose tissue described over the past 10 years is the realization that adipose tissue in general and adipocytes in particular have the potential to be a rich source of a vast array of secretory proteins. Since infiltrating immune cells, most notably monocytes, are known to have a profound effect on adipocytes, interest in the stromal fraction of adipose tissue has increased considerably. These stromal components consist of fibroblastlike preadipocytes, endothelial cells, vascular smooth muscle cells, neurons, and immune cells. It is currently not established how these stromal components interact with adipocytes during adipose tissue expansion. The nature of the local endothelium, a key constituent of the vasculature, has received limited attention to date.Destruction of local endothelial cells results in a reduction in fat mass during times of excess caloric intake independent of food intake (2,30,38). Functioning through an as yet unidentified mechanism, such a reduction in fat mass results in decreased levels of steatosis in the liver and enhanced glucose tolerance. These metabolic improvements are somewhat surprising, considering that the forced reduction of fat mass in the context of lipodystrophies leads to a decrease rather than an increase in systemic insulin sensitivity (30,36). These observations highlight the need for a better understanding of the adipose tissue vasculature.During times of positive energy balance, adipose tissue absorbs the energy surplus by increasing both cell size and number. The ability of adipose tissue to expand critically depends on vascular outgrowth (4). At the same time, the increased adipocyte size requires oxygen to diffuse over longer distances prior to reaching adipocyte mitochondria; this is evident by a decreased partial oxygen pressure (20 mmHg versus 40 mmHg) in obese versus lean mice, respectively (20,37,53). Hypoxia in obese adipose tissue has been observed by several groups and results in the induction of the key hypoxia regulator, hypoxia-inducible factor 1 (HIF1) (20,37,49,53). HIF1 is a heterodimer consisting of the oxygen-regulated HIF1␣ subunit and the constitutively expressed HIF1␤ ...

Heart failure with preserved ejection fraction (HFpEF) is a common, morbid, and mortal syndrome for which there are no evidence-based therapies. Here, we report that concomitant metabolic and hypertensive stress in mice elicited by a combination of high fat diet (HFD) and constitutive nitric oxide (NO) synthase inhibition by N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulates the numerous systemic and cardiovascular features of human HFpEF. One of the unfolded protein response (UPR) effectors, the spliced form of X-box binding protein 1 (Xbp1s), was reduced in the myocardium of both experimental and human HFpEF. Mechanistically, the decrease in Xbp1s resulted from increased inducible NO synthase (iNOS) activity and S-nitrosylation of endonuclease inositol-requiring protein 1α (IRE1α), culminating in defective Xbp1 splicing. Pharmacological or genetic suppression of iNOS, or cardiomyocyte-restricted overexpression of Xbp1s, each ameliorated the HFpEF phenotype. We have unveiled iNOS-driven dysregulation of IRE1α-Xbp1s as a crucial mechanism of cardiomyocyte dysfunction in HFpEF.

Obese fat pads are frequently undervascularized and hypoxic, leading to increased fibrosis, inflammation, and ultimately insulin resistance. We hypothesized that VEGF-A–induced stimulation of angiogenesis enables sustained and sufficient oxygen and nutrient exchange during fat mass expansion, thereby improving adipose tissue function. Using a doxycycline (Dox)-inducible adipocyte-specific VEGF-A overexpression model, we demonstrate that the local up-regulation of VEGF-A in adipocytes improves vascularization and causes a “browning” of white adipose tissue (AT), with massive up-regulation of UCP1 and PGC1α. This is associated with an increase in energy expenditure and resistance to high fat diet-mediated metabolic insults. Similarly, inhibition of VEGF-A–induced activation of VEGFR2 during the early phase of high fat diet-induced weight gain, causes aggravated systemic insulin resistance. However, the same VEGF-A–VEGFR2 blockade in ob/ob mice leads to a reduced body-weight gain, an improvement in insulin sensitivity, a decrease in inflammatory factors, and increased incidence of adipocyte death. The consequences of modulation of angiogenic activity are therefore context dependent. Proangiogenic activity during adipose tissue expansion is beneficial, associated with potent protective effects on metabolism, whereas antiangiogenic action in the context of preexisting adipose tissue dysfunction leads to improvements in metabolism, an effect likely mediated by the ablation of dysfunctional proinflammatory adipocytes.

Adiponectin is an adipocyte-specific factor, first described in 1995. Over the past two decades, numerous studies have elucidated the physiological functions of adiponectin in obesity, diabetes, inflammation, atherosclerosis, and cardiovascular disease. Adiponectin, elicited through cognate receptors, suppresses glucose production in the liver and enhances fatty acid oxidation in skeletal muscle, which together contribute to a beneficial metabolic action in whole body energy homeostasis. Beyond its role in metabolism, adiponectin also protects cells from apoptosis and reduces inflammation in various cell types via receptor-dependent mechanisms. Adiponectin, as a fat-derived hormone, therefore fulfills a critical role as an important messenger to communicate between adipose tissue and other organs. A better understanding of adiponectin actions, including the pros and cons, will advance our insights into basic mechanisms of metabolism and inflammation, and potentially pave the way toward novel means of pharmacological intervention to address pathophysiological changes associated with diabetes, atherosclerosis, and cardiometabolic disease.

SUMMARY The hexosamine biosynthetic pathway (HBP) generates UDP-GlcNAc (uridine diphosphate N-acetylglucosamine) for glycan synthesis and O-linked GlcNAc (O-GlcNAc) protein modifications. Despite the established role of the HBP in metabolism and multiple diseases, regulation of the HBP remains largely undefined. Here, we show that spliced X-box binding protein 1 (Xbp1s), the most conserved signal transducer of the unfolded protein response (UPR), is a direct transcriptional activator of the HBP. We demonstrate that the UPR triggers HBP activation via Xbp1s-dependent transcription of genes coding for key, rate-limiting enzymes. We further establish that this previously unrecognized UPR-HBP axis is triggered in a variety of stress conditions. Finally, we demonstrate a physiologic role for the UPR-HBP axis, by showing that acute stimulation of Xbp1s in heart by ischemia/reperfusion confers robust cardioprotection in part through induction of the HBP. Collectively, these studies reveal that Xbp1s couples the UPR to the HBP to protect cells under stress.

Summary Chronic inflammation constitutes an important link between obesity and its pathophysiological sequelae. In contrast to the belief that inflammatory signals exert a fundamentally negative impact on metabolism, we show that pro-inflammatory signaling in the adipocyte is in fact required for proper adipose tissue remodeling and expansion. Three mouse models with an adipose tissue-specific reduction in pro-inflammatory potential were generated that display a reduced capacity for adipogenesis in vivo, while the differentiation potential is unaffected in vitro. Upon high fat diet exposure, the expansion of visceral adipose tissue is prominently affected. This is associated with decreased intestinal barrier function, increased hepatic steatosis and metabolic dysfunction. An impaired local pro-inflammatory response in the adipocyte leads to increased ectopic lipid accumulation, glucose intolerance and systemic inflammation. Adipose tissue inflammation is therefore an adaptive response that enables safe storage of excess nutrients and contributes to a visceral depot barrier that effectively filters gut-derived endotoxin.