Featured Articles

Volume 5 | No. 10 | October 2016

α-Melanocyte stimulating hormone promotes muscle glucose uptakeEnriori, Chen et al. set out to determine if peripheral α-melanocyte stimulating hormone (α-MSH) plays a role in glucose homeostasis and test the hypothesis that the pituitary is able to sense a physiological increase in circulating glucose and responds by secreting α-MSH. They show that glucose stimulates α-MSH production and increases circulating concentrations, which increases muscle glucose uptake through the activation of the melanocortin 5 receptor (MC5R)-PKA pathway.

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Estrogens modulate ventrolateral ventromedial hypothalamic glucose-inhibited neuronsSantiago and colleagues show a sexual dimorphism in nonadapting ventrolateral ventromedial hypothalamic nucleus (VL-VMN) glucose-inhibited (GI) neurons, which is apparently due to organizational effects since differences are present in the absence of estrogens. 17β-estradiol (17βE) affects the glucose sensing machinery (AMP-activated protein kinase) in both non-adapting GI and adapting GI (AdGI) neurons of both sexes. The data suggest that sex differences observed in VL-VMN nonadapting GI neurons and 17βE effects on the glucose sensitivity of both nonadaptive GI and AdGI neurons may underlie the observed sex differences in hypoglycemia detection and counterregulation.

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The satiating hormone amylin enhances neurogenesis in the area postremaAmylin is a pancreatic hormone whose role in the control of food intake and energy metabolism is well characterized. Liberini and colleagues demonstrate that amylin regulates genes involved in pathways and processes that drive neurogenesis in the adult mammalian brain. Their results also show an in vivo increase in the number of newly proliferating area postrema (AP)-cells after chronic amylin treatment. Amylin has the potential to commit the AP adult-born cells to a neuronal fate.

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Defining a novel leptin-melanocortin-kisspeptin pathwayRecent reports documented that earlier puberty is linked to a higher risk of cardio-metabolic disease, including hypertension and type-2 diabetes. The data of Manfredi-Lozano, Roa et al. in wild type and genetically modified rodent models provide a novel mechanistic insight into the melanocortin regulation of pubertal maturation in the female by documenting a discernible leptin → α-melanocyte stimulating hormone → kisspeptin → gonadotropin-releasing hormone pathway, which appears to play an important role in the metabolic control of puberty.

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Mechanisms underlying prorenin actions on hypothalamic neurons implicated in cardiometabolic controlPitra and colleagues provide novel evidence that indicates that prorenin stimulates hypothalamic magnocellular neurosecretory cells and presympathetic paraventricular nucleus neuronal activity via distinct, angiotensin II-independent and dependent mechanisms, respectively, and that these actions involve suppression of a voltage gated K+ channel in a Ca2+-dependent manner. Elucidating the basic cellular targets and mechanisms by which prorenin and its receptor regulate neuronal activity within the hypothalamus is fundamental information required for a more comprehensive understanding of how the central RAS influences sympatho-humoral regulation of cardiovascular and metabolic functions.

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Reprogramming the body weight set point reverts extreme obesityChhabra and colleagues demonstrate that proopiomelanocortin (Pomc)-deficiency in the arcuate (Arc) nucleus increases fat mass and the ratio of fat to lean mass, and it impairs the function of leptin to reduce body weight and food intake independently of body weight. Rescue of ArcPomc expression in weight-matched mice with ArcPomc silencing, whether or not there is a history of previous obesity, reestablishes normal energy homeostasis and body weight set point under ad libitum feeding conditions by correcting the abnormal body composition and restoring leptin sensitivity. Massive hyperleptinemia induced by PASylated leptin administration prevents this normalization by blocking the complete restoration of ArcPomc expression. A strong reciprocal association between leptin levels and hypothalamic Pomc in the regulation of energy homeostasis is revealed.

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Adiponectin potentiates the acute effects of leptin in arcuate Pomc neuronsSun, Gao, Yao et al. test the hypothesis that adiponectin and leptin may synergistically activate melanocortin neurons. They utilize transgenic and Cre-Lox technology to identify neuropeptide Y/Agouti-related peptide (NPY/AgRP) and proopiomelanocortin (Pomc) neurons, which express leptin receptors. They show that leptin and adiponectin modulate neuronal excitability of melanocortin neurons in an additive manner, an activity that requires phosphoinositide-3-kinase (PI3K) signaling. The data provide evidence for PI3K as a substrate for both leptin and adiponectin to regulate metabolism via melanocortin activity.

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Physiological role for leptin in the control of thermal conductanceKaiyala and colleagues report that physiological leptin levels play a role in conferring the ability to defend normothermia during cold exposure. This effect does not stem from increased energy expenditure, the induction of BAT, or increased ambulatory activity levels, but is due, in part, to an effect of leptin to reduce heat loss. These findings identify a new physiological role for leptin as a mediator of reduced heat dissipation elicited by cold exposure, an efficient and economical homeostatic strategy for maintenance of core temperature in light of the extremely high metabolic cost of matching energy intake to markedly elevated energy expenditure levels during cold exposure in small mammals.

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TNP ameliorates diet induced obesity and insulin resistanceGoshal and colleagues show that pharmacologic inhibition of the inositol pyrophosphate pathway ameliorates obesity and insulin resistance in diet induced obesity (DIO) mice. TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine] fails to reduce weight gain in high fat diet-fed inositol hexakisphosphate kinase-1 (IP6K1)-knock out mice. This suggests that the compound reduces body weight specifically via IP6K1 inhibition. Even a single-dose of TNP enhances insulin sensitivity in DIO mice by increasing Akt activity in metabolic tissues. TNP reduces body weight, at least in part, by augmenting adipose tissue browning/thermogenesis mediated energy expenditure.

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Impact of statistical models on the prediction of type 2 diabetes Although epidemiological studies have reported numerous risk factors for type 2 diabetes, the predictive performances of statistical models based on these predictors still need to be improved. The study of Yengo and colleagues highlights that few biomarkers with an efficient combination as risk scores can improve the identification of incident type 2 diabetes cases, especially in those poorly recognized by classical clinical risk factors. The clinical use of such biomarkers is important for the development of early interventions for the prevention of type 2 diabetes, involving changes in life style and pharmacotherapy.

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Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolismBranched-chain amino acids (BCAAs) have been identified as potential contributors to insulin resistance. The data of Lerin and colleagues suggest that perturbations in BCAA metabolism may contribute to metabolic phenotypes associated with insulin resistance and type 2 diabetes risk. The study also suggests that searching for metabolic phenotypes in carriers of methylmalonyl-CoA mutase mutations would be relevant for understanding disease pathogenesis and guiding clinical management strategies.

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Depot specific differences in the adipogenic potential of precursorsThe extracellular matrix (ECM) is known to play an important role in terminal differentiation of preadipocytes. Given this and the known differences in the response of different adipose depots, Grandl and colleagues employ a strategy for deriving the extracellular matrix from primary cells of different adipose depots to investigate its role in adipose precursor differentiation. They demonstrate that the potential for depot-specific adipocyte precursors to form mature adipocytes is mainly dependent on the ECM. They also find that integration of the necessary ECM to cell signaling cues might in part be mediated through transmembrane protein Flotillin 2.

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Genetic backgrounds determine brown remodeling of white fatGenetic background is a major contributing factor in the susceptibility to diet induced obesity and type 2 diabetes. The study of Ferrannini, Namwanje et al. reveals that genetic background is a significant factor in regulating brown remodeling of white adipose tissue in a strain specific and depot-specific manner. They identify novel candidates in regulating adipose tissue plasticity, particularly Hoxc10 as a “browning brake” in subcutaneous white adipose tissue. The expectation of the authors is that the coordination between activators and repressors in brown remodeling determines the physiological consequences of adipose tissue and thus may provide novel insights for obesity treatment.

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Adipose tissue (P)RR regulates insulin sensitivity, fat mass and body weightThe study of patients suffering from obesity and obese rodent models has shed light on the importance of the renin-angiotensin system (RAS) in the development of obesity. The prorenin/renin receptor [(P)RR] is a component of the RAS where its main role is to increase the catalytic activity of renin. The results of Shamansurova, Tan et al. suggest that adipose tissue (P)RR is involved in the development of obesity and its associated complications. Suppression of the (P)RR, specifically in adipose tissue, produces a clear phenotype of reduced body weight and fat masses as well as improved adipose tissue structure and insulin sensitivity.

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Myocardin-related transcription factor A (MRTFA) regulates the fate of bone marrow mesenchymal stem cellsAdipogenesis and osteogenesis are mutually exclusive processes during mesenchymal stem cell differentiation, and appropriate balance between them is essential for maintaining homeostasis in bone marrow. Once the precisely regulated balance is disturbed, various metabolic-related diseases develop. The study of Bian and colleagues identifies myocardin-related transcription factor A as a novel regulator of skeletal homeostasis by controlling the balance between adipogenic and osteogenic differentiation in bone marrow stem cells, and thus holds promise as a potential target for therapeutic intervention for osteoporosis.

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Knockdown of ATP citrate lyase in pancreatic beta cells does not inhibit insulin secretion or glucose fluxIn addition to ATP production, an important role of mitochondria in the pancreatic beta cell is the net synthesis of citric acid cycle intermediates that are exported to the cytosol where they are converted to numerous other metabolites that stimulate and/or support insulin secretion. Azzouny and colleagues show that the flux of glucose into cytosolic short chain acyl-CoAs is maintained in pure beta cells in the presence of inhibition of ATP citrate lyase. The only known pathway other than through the ATP citrate lyase reaction leading to the formation of short chain acyl-CoAs in the cytosol is the acetoacetate pathway. The results establish the role of the acetoacetate pathway in insulin secretion.

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The regulator of G-protein signaling RGS16 promotes insulin secretion and β-cell proliferationThe results of Vivot and colleagues demonstrate that in pancreatic β-cells, RGS16 limits the inhibitory effect of somatostatin (SST) on insulin secretion and β-cell proliferation by dampening Gαi/o activity downstream of SST receptor and, consequently, increasing intracellular cAMP levels. Since RGS16 expression is strongly stimulated by glucose, these observations suggest a role for RGS16 in β-cell compensation to increased metabolic demand whereby releasing a tonic “break” on insulin secretion and β-cell proliferation enable the β-cell to quickly adjust to a changing metabolic environment.

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Inhibition of RORα/γ suppresses atherosclerosis via inhibition of both cholesterol absorption and inflammationRAR-related orphan receptors (ROR) are members of the NR superfamily that are known to be involved in inflammatory and metabolic processes. The data of Billon and colleagues demonstrate that pharmacological suppression of RORα and RORγ activity suppresses atherosclerosis in a mouse model. RORα and RORγ can be targeted to modulate the immune system and cholesterol excretion, two main risk factors that lead to atherosclerosis.

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Roux-en-Y gastric bypass surgery is effective in fibroblast growth factor-21 deficient miceFibroblast growth factor 21 (FGF21) has profound beneficial effects on body weight and metabolism in preclinical obesity models. Morrison and colleagues show that FGF21-signaling is not a critical single factor required for Roux-en-Y gastric bypass surgery (RYGB) to lower body weight and improve glycemic control but may play a minor role in food choice and locomotor activity. The findings in this study do not rule out the possibility that FGF21 acts as an important co-factor with other putative mechanisms. If FGF21 is not directly involved in RYGB’s effects on energy balance, it might be useful as an adjuvant future therapy in patients with failed or suboptimal bariatric surgery outcomes.

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Fibroblast activation protein (FAP) as a novel metabolic targetFibroblast activation protein (FAP) is a serine protease belonging to a S9B prolyl oligopeptidase subfamily and has been recently reported to regulate degradation of FGF21, a potent metabolic hormone. Sánchez-Garrido and colleagues demonstrate that the FAP inhibitor, talabostat (TB), as a single agent, provides body weight reduction, glucose control, insulin sensitization, cholesterol lowering, and increased energy expenditure associated with elevated plasma fibroblast growth factor 21 (FGF21) levels. The absence of any effect on glucose or weight reduction in FGF21-deficient mice supports their hypothesis that FGF21 is a central mediator of the efficacy delivered by TB therapy. All of these effects are substantially attenuated in lean mice suggesting the ability to selectively inhibit FAP without overt toxicity.

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The 60 Second Metabolist
In this section authors briefly report on their work recently published in Molecular Metabolism.

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Giles Yeo
University of Cambridge, UK
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