Adiponectin, the past two decades Wang, Zhao V; Scherer, Philipp E
Journal of molecular cell biology,
04/2016, Letnik:
8, Številka:
2
Journal Article
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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.
...the age-adjusted levels of LPS significantly vary in different ethnic groups, being the highest in South Asians. ...a “leaky gut” condition can be induced by SARS-CoV-2 infection in seemingly ...non-compromised individuals as well. ...we have to differentiate between the “preexisting” and “induced” endotoxemia in COVID-19 patients. Amino acids are strongly involved in the regulation of the intestinal epithelial barrier function 19; hence, a reduction of ACE2 content induced by interactions of these receptors with SARS-CoV-2 will significantly impair the integrity of the intestinal barrier. ...it was reported that ACE2 exhibits a protective effect against LPS-induced acute lung injury in mice 21; hence, viral suppression of ACE2 can lead to a stronger inflammatory responses in lungs.
Once considered divine retribution for sins, comorbidities of obesity (metabolic syndrome) are today attributed to obesity-induced metabolic defects. Here, we propose that obesity and hyperleptinemia ...protect lipid-intolerant nonadipose organs against lipotoxic lipid spillover during sustained caloric surplus. Metabolic syndrome is ascribed to lipotoxicity caused by age-related resistance to antilipotoxic protection by leptin.
The important role of mitochondria in the regulation of white adipose tissue (WAT) remodeling and energy balance is increasingly appreciated. The remarkable heterogeneity of the adipose tissue stroma ...provides a cellular basis to enable adipose tissue plasticity in response to various metabolic stimuli. Regulating mitochondrial function at the cellular level in adipocytes, in adipose progenitor cells (APCs), and in adipose tissue macrophages (ATMs) has a profound impact on adipose homeostasis. Moreover, mitochondria facilitate the cell-to-cell communication within WAT, as well as the crosstalk with other organs, such as the liver, the heart, and the pancreas. A better understanding of mitochondrial regulation in the diverse adipose tissue cell types allows us to develop more specific and efficient approaches to improve adipose function and achieve improvements in overall metabolic health.
Regulation of mitochondrial activity in white adipocytes is an essential component of adipose tissue and systemic metabolic homeostasis.Additional cells in adipose tissue (progenitors, endothelial cells, immune cells) are also critically regulated by mitochondrial activity in the respective cells.Intercellular and interorgan exchange of mitochondria is an important new mechanism of information exchange between cells and tissues.A key feature of the regulation of mitochondrial activity in adipose tissue is the choice of the preferred carbon source in the respective cells within adipose tissue, that is, use of carbohydrate through glycolysis versus use of lipids for oxidative phosphorylation.The choice of substrate for energy production exerts a profound impact on the characteristic metabolic features of the various cell types that make up adipose tissue and their impact on tissue and systemic energy homeostasis.
Adipocytes undergo intense energetic stress in obesity resulting in loss of mitochondrial mass and function. We have found that adipocytes respond to mitochondrial stress by rapidly and robustly ...releasing small extracellular vesicles (sEVs). These sEVs contain respiration-competent, but oxidatively damaged mitochondrial particles, which enter circulation and are taken up by cardiomyocytes, where they trigger a burst of ROS. The result is compensatory antioxidant signaling in the heart that protects cardiomyocytes from acute oxidative stress, consistent with a preconditioning paradigm. As such, a single injection of sEVs from energetically stressed adipocytes limits cardiac ischemia/reperfusion injury in mice. This study provides the first description of functional mitochondrial transfer between tissues and the first vertebrate example of “inter-organ mitohormesis.” Thus, these seemingly toxic adipocyte sEVs may provide a physiological avenue of potent cardio-protection against the inevitable lipotoxic or ischemic stresses elicited by obesity.
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•Mitochondrial stress stimulates adipocyte sEV release•Adipocyte stress-induced sEVs are enriched with oxidatively damaged mitochondria•Mitochondria in sEVs from stressed adipocytes induce a burst of ROS in cardiac tissue•The adipocyte-derived pro-oxidant signal protects the heart through hormesis
Crewe et al. report that adipocytes release sEVs containing damaged mitochondria in response to energetic stress, such as seen in chronic obesity. The sEV-associated mitochondria induce transient mitochondrial oxidative stress in cardiac tissue, resulting in an antioxidant response. Adipocyte sEVs thereby precondition the heart to protect against ischemia/reperfusion injury.
FGF21, a member of the fibroblast growth factor (FGF) superfamily, has recently emerged as a regulator of metabolism and energy utilization. However, the exact mechanism(s) whereby FGF21 mediates its ...actions have not been elucidated. There is considerable evidence that insulin resistance may arise from aberrant accumulation of intracellular lipids in insulin-responsive tissues due to lipotoxicity. In particular, the sphingolipid ceramide has been implicated in this process. Here, we show that FGF21 rapidly and robustly stimulates adiponectin secretion in rodents while diminishing accumulation of ceramides in obese animals. Importantly, adiponectin-knockout mice are refractory to changes in energy expenditure and ceramide-lowering effects evoked by FGF21 administration. Moreover, FGF21 lowers blood glucose levels and enhances insulin sensitivity in diabetic Lepob/ob mice and diet-induced obese (DIO) mice only when adiponectin is functionally present. Collectively, these data suggest that FGF21 is a potent regulator of adiponectin secretion and that FGF21 critically depends on adiponectin to exert its glycemic and insulin sensitizing effects.
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•FGF21 potently stimulates adiponectin secretion•Adiponectin is critical for the FGF21-induced increases in energy expenditure•Adiponectin is requisite for FGF21 to improve glucose homeostasis in obese mice•Like adiponectin, TZDs and FGF21 decrease ceramide accumulation in obese mice
The hexosamine biosynthetic pathway (HBP) generates uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) 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.
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•Ischemia/reperfusion (I/R) in heart activates spliced X-box binding protein 1 (Xbp1s)•Xbp1s triggers expression of multiple enzymes of the hexosamine biosynthetic pathway•Xbp1s increases O-GlcNAc modification on cardiac proteins•Xbp1s protects heart from I/R injury
Induction of Xbp1s, signal transducer of the unfolded protein response, protects heart from ischemia/reperfusion-induced cardiac injury by activating the hexosamine biosynthetic pathway.
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 proinflammatory 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 proinflammatory potential were generated that display a reduced capacity for adipogenesis in vivo, while the differentiation potential is unaltered 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 proinflammatory 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.
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•Adipocyte inflammation facilitates adipose tissue expansion and remodeling•Suppressed adipocyte inflammation leads to adipose tissue dysfunction•Suppressed adipocyte inflammation leads to systemic metabolic disturbances•Mesenteric adipose tissue is important for proper intestinal barrier function
Contrary to the idea that inflammation plays a negative role in metabolism, Wernstedt Asterholm and colleagues show that proinflammatory signals in the adipocyte are required for proper adipose tissue remodeling and expansion. Adipose tissue inflammation plays an adaptive response for adipocyte expansion and proper intestinal barrier function.
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