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Although classically appreciated for their role as the powerhouse of the cell, the metabolic functions of mitochondria reach far beyond bioenergetics. In this Review, we discuss how mitochondria catabolize nutrients for energy, generate biosynthetic precursors for macromolecules, compartmentalize metabolites for the maintenance of redox homeostasis and function as hubs for metabolic waste management. We address the importance of these roles in both normal physiology and in disease.

Melanocortin-4 receptor-expressing neurons in the paraventricular nucleus of the hypothalamus (PVH MC4R ) integrate hunger-promoting and hunger-suppressing signals to regulate satiety. Food consumption-evoked responses in PVH MC4R neurons increase gradually during meal consumption to promote satiety, and disrupting this process drives massive obesity. These critical satiety neurons are strongly affected by a high-fat diet, yet the impact on their functional properties remains unknown. We used fiber photometry to track PVH MC4R neurons’ responses to the consumption of drops of milkshake in animals fed a chow diet or a high-fat diet (HFD), both after obesity was established and after its reversal. PVH MC4R neurons in HFD-fed animals showed greater consumption-evoked responses than chow-fed animals at the early stages of meal consumption, and these responses did not increase further during the meal. HFD-fed animals also showed reduced licking vigor and motivation to consume milkshake. Switching HFD-fed obese animals to a normal chow diet (NCD) re-engaged the motivation to consume milkshake, partially restored early-meal neural responses to a lower level, but did not restore the increase in consumption-evoked response magnitude across the meal. These findings highlight functional alterations in hypothalamic satiety-promoting neurons in obesity and provide insight into the pathological neural consequences of an obesogenic environment.

Amyloid deposits in pancreatic islets, mainly formed by human islet amyloid polypeptide (hIAPP) aggregation, have been associated with loss of β-cell mass and function, and are a pathological hallmark of type 2 diabetes (T2D). Treatment with chaperones has been associated with a decrease in endoplasmic reticulum stress leading to improved glucose metabolism. The aim of this work was to investigate whether the chemical chaperone 4-phenylbutyrate (PBA) prevents glucose metabolism abnormalities and amyloid deposition in obese agouti viable yellow (A vy ) mice that overexpress hIAPP in β cells (A vy hIAPP mice), which exhibit overt diabetes. Oral PBA treatment started at 8 weeks of age, when A vy hIAPP mice already presented fasting hyperglycemia, glucose intolerance, and impaired insulin secretion. PBA treatment strongly reduced the severe hyperglycemia observed in obese A vy hIAPP mice in fasting and fed conditions throughout the study. This effect was paralleled by a decrease in hyperinsulinemia. Importantly, PBA treatment reduced the prevalence and the severity of islet amyloid deposition in A vy hIAPP mice. Collectively, these results show that PBA treatment elicits a marked reduction of hyperglycemia and reduces amyloid deposits in obese and diabetic mice, highlighting the potential of chaperones for T2D treatment.

Brown and beige adipose tissue are emerging as distinct endocrine organs. These tissues are functionally associated with skeletal muscle, adipose tissue metabolism and systemic energy expenditure, suggesting an interorgan signaling network. Using metabolomics, we identify 3-methyl-2-oxovaleric acid, 5-oxoproline, and β-hydroxyisobutyric acid as small molecule metabokines synthesized in browning adipocytes and secreted via monocarboxylate transporters. 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid induce a brown adipocyte-specific phenotype in white adipocytes and mitochondrial oxidative energy metabolism in skeletal myocytes both in vitro and in vivo. 3-methyl-2-oxovaleric acid and 5-oxoproline signal through cAMP-PKA-p38 MAPK and β-hydroxyisobutyric acid via mTOR. In humans, plasma and adipose tissue 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid concentrations correlate with markers of adipose browning and inversely associate with body mass index. These metabolites reduce adiposity, increase energy expenditure and improve glucose and insulin homeostasis in mouse models of obesity and diabetes. Our findings identify beige adipose-brown adipose-muscle physiological metabokine crosstalk. Beige and brown fat may influence systemic metabolism through secreted signals. Here the authors identify a panel of metabolites secreted from beige and brown fat cells, which signal to influence fat tissue and skeletal muscle metabolism and have anti-obesity effects in mouse models of obesity and diabetes.

Hyperplastic expansion of white adipose tissue (WAT) relies in part on the proliferation of adipocyte precursor cells residing in the stromal vascular cell fraction (SVF) of WAT. This study reveals a circadian clock- and feeding-induced diurnal pattern of cell proliferation in the SVF of visceral and subcutaneous WAT in vivo, with higher proliferation of visceral adipocyte progenitor cells subsequent to feeding in lean mice. Fasting or loss of rhythmic feeding eliminates this diurnal proliferation, while high fat feeding or genetic disruption of the molecular circadian clock modifies the temporal expression of proliferation genes and impinges on diurnal SVF proliferation in eWAT. Surprisingly, high fat diet reversal, sufficient to reverse elevated SVF proliferation in eWAT, was insufficient in restoring diurnal patterns of SVF proliferation, suggesting that high fat diet induces a sustained disruption of the adipose circadian clock. In conclusion, the circadian clock and feeding simultaneously impart dynamic, regulatory control of adipocyte progenitor proliferation, which may be a critical determinant of adipose tissue expansion and health over time. During the expansion of adipose tissue adipocyte progenitor cells proliferate and undergo adipogenesis. Here, the authors show that adipocyte progenitor cell proliferation in visceral adipose tissue has a diurnal pattern, which is dependent on both energy intake and the circadian clock.

Background: Two brown-like adipocytes, including classical brown adipocytes from brown adipose tissues and beige cells from white adipose tissues, regulate thermogenesis. The developmental and functional induction of brown-like cells provides a defense against obesity and associated metabolic diseases. Our previous study suggests dietary luteolin can improve diet-induced obesity and insulin resistance in mice. Here we further elucidated the action of the natural flavonoid on energy expenditure and adaptive thermogenesis. Methods: Five-week-old male C57BL/6 mice were fed low-fat diet (LFD), high-fat diet (HFD) and HFD supplemented with 0.01% luteolin. After 12 weeks, their energy expenditure were detected using a combined indirect calorimetry system. Moreover, thermogenic program and associated molecular regulators were assessed in adipose tissues. In another independent study, even-aged mice were fed LFD and luteolin-containing LFD for 12 weeks, and their energy expenditure and thermogenic program were also investigated. Finally, differentiated primary brown and subcutaneous adipocytes were used to identify the critical participation of AMPK/PGC1α signaling in luteolin-regulated browning and thermogenesis. Results: In mice fed either HFD or LFD, dietary luteolin supplement increased oxygen consumption, carbon dioxide production and respiratory exchange ratio. The enhancement in energy expenditure was accompanied by the upregulation of thermogenic genes in brown and subcutaneous adipose tissues. Meanwhile, several important AMPK/PGC1α signaling molecules were activated by dietary luteolin in the tissues. Further, luteolin treatment directly elevated thermogenic gene expressions and activated AMPK/PGC1α signaling in differentiated primary brown and subcutaneous adipocytes, whereas AMPK inhibitor Compound C reversed the efficiencies. Conclusions: Dietary luteolin activated browning and thermogenesis through an AMPK/PGC1α pathway-mediated mechanism.

Perturbations in metabolic processes are associated with diseases such as obesity, type 2 diabetes mellitus, certain infections and some cancers. A resurgence of interest in creatine biology is developing, with new insights into a diverse set of regulatory functions for creatine. This resurgence is primarily driven by technological advances in genetic engineering and metabolism as well as by the realization that this metabolite has key roles in cells beyond the muscle and brain. Herein, we highlight the latest advances in creatine biology in tissues and cell types that have historically received little attention in the field. In adipose tissue, creatine controls thermogenic respiration and loss of this metabolite impairs whole-body energy expenditure, leading to obesity. We also cover the various roles that creatine metabolism has in cancer cell survival and the function of the immune system. Renewed interest in this area has begun to showcase the therapeutic potential that lies in understanding how changes in creatine metabolism lead to metabolic disease.Creatine is well known to have a key role in energy buffering; however, new work is showing that creatine also has roles in diverse cell types and physiological conditions that are distinct from this classic role. This Review discusses the role of creatine in adipocyte thermogenesis, immunity and cancer cell survival.

Although it is well-established that reductions in the ratio of insulin to glucagon in the portal vein have a major role in the dysregulation of hepatic glucose metabolism in type-2 diabetes 1 – 3 , the mechanisms by which glucagon affects hepatic glucose production and mitochondrial oxidation are poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation—all of which are mediated by stimulation of the inositol triphosphate receptor 1 (INSP3R1). In rats and mice, chronic physiological increases in plasma glucagon concentrations increased mitochondrial oxidation of fat in the liver and reversed diet-induced hepatic steatosis and insulin resistance. However, these effects of chronic glucagon treatment—reversing hepatic steatosis and glucose intolerance—were abrogated in Insp3r1 (also known as Itpr1 )-knockout mice. These results provide insights into glucagon biology and suggest that INSP3R1 may represent a target for therapies that aim to reverse nonalcoholic fatty liver disease and type-2 diabetes. A role and mechanism of action are identified for INSP3R1 in the stimulation of hepatic gluconeogenesis and mitochondrial oxidation by glucagon, suggesting that INSP3R1 may be a target for ameliorating dysregulation of hepatic glucose metabolism.

ObjectiveObesity significantly elevates the odds of developing mood disorders. Chronic consumption of a saturated high-fat diet (HFD) elicits anxiodepressive behavior in a manner linked to metabolic dysfunction and neuroinflammation in mice. Dietary omega-3 polyunsaturated fatty acids (n-3 PUFA) can improve both metabolic and mood impairments by relieving inflammation. Despite these findings, the effects of n-3 PUFA supplementation on energy homeostasis, anxiodepressive behavior, brain lipid composition, and gliosis in the diet-induced obese state are unclear.MethodsMale C57Bl/6J mice were fed a saturated high-fat diet (HFD) or chow for 20 weeks. During the last 5 weeks mice received daily gavage (“supplementation”) of fish oil (FO) enriched with equal amounts of docosahexaenoic (DHA) and eicosapentaenoic acid (EPA) or control corn oil. Food intake and body weight were measured throughout while additional metabolic parameters and anxiety- and despair-like behavior (elevated-plus maze, light–dark box, and forced swim tasks) were evaluated during the final week of supplementation. Forebrain lipid composition and markers of microglia activation and astrogliosis were assessed by gas chromatography–mass spectrometry and real-time PCR, respectively.ResultsFive weeks of FO supplementation corrected glucose intolerance and attenuated hyperphagia in HFD-induced obese mice without affecting adipose mass. FO supplementation also defended against the anxiogenic and depressive-like effects of HFD. Brain lipids, particularly anti-inflammatory PUFA, were diminished by HFD, whereas FO restored levels beyond control values. Gene expression markers of brain reactive gliosis were supressed by FO.ConclusionsSupplementing a saturated HFD with FO rich in EPA and DHA corrects glucose intolerance, inhibits food intake, suppresses anxiodepressive behaviors, enhances anti-inflammatory brain lipids, and dampens indices of brain gliosis in obese mice. Together, these findings support increasing dietary n-3 PUFA for the treatment of metabolic and mood disturbances associated with excess fat intake and obesity.