GPR17 gene disruption does not alter food intake or glucose homeostasis in mice

Mastaitis, Jason; Min, Soo Kee; Elvert, Ralf; Kannt, Aimo; Xin, Yurong; Ochoa, Francisca; Gale, Nicholas W.; Valenzuela, David M.; Murphy, Andrew J.; Yancopouloš, George D.; Gromada, Jesper

doi:10.1073/pnas.1424968112

Cited by 17 publications

(16 citation statements)

References 26 publications

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“…In addition, these neurons abundantly express the G-protein-coupled receptor GPR17 [529]. This molecule has become the source of recent controversy whether it possesses significant orexigenic effects [530] or not [531]. A distinct group of first-order arcuate neurons produces anorexigenic (appetite-suppressing) neuropeptides, chiefly POMC and cocaine-and amphetamine-regulated transcript (CART).…”

Section: Normal Effects Of Central Insulin On the Regulation Of Appetmentioning

confidence: 99%

Imbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forward

Williams

2016

Atherosclerosis

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The growing worldwide prevalence of overnutrition and underexertion threatens the gains that we have made against atherosclerotic cardiovascular disease and other maladies. Chronic overnutrition causes the atherometabolic syndrome, which is a cluster of seemingly unrelated health problems characterized by increased abdominal girth and body-mass index, high fasting and postprandial concentrations of cholesterol- and triglyceride-rich apoB-lipoproteins (C-TRLs), low plasma HDL levels, impaired regulation of plasma glucose concentrations, hypertension, and a significant risk of developing overt type 2 diabetes mellitus (T2DM). In addition, individuals with this syndrome exhibit fatty liver, hypercoagulability, sympathetic overactivity, a gradually rising set-point for body adiposity, a substantially increased risk of atherosclerotic cardiovascular morbidity and mortality, and--crucially--hyperinsulinemia. Many lines of evidence indicate that each component of the atherometabolic syndrome arises, or is worsened by, pathway-selective insulin resistance and responsiveness (SEIRR). Individuals with SEIRR require compensatory hyperinsulinemia to control plasma glucose levels. The result is overdrive of those pathways that remain insulin-responsive, particularly ERK activation and hepatic de-novo lipogenesis (DNL), while carbohydrate regulation deteriorates. The effects are easily summarized: if hyperinsulinemia does something bad in a tissue or organ, that effect remains responsive in the atherometabolic syndrome and T2DM; and if hyperinsulinemia might do something good, that effect becomes resistant. It is a deadly imbalance in insulin action. From the standpoint of human health, it is the worst possible combination of effects. In this review, we discuss the origins of the atherometabolic syndrome in our historically unprecedented environment that only recently has become full of poorly satiating calories and incessant enticements to sit. Data are examined that indicate the magnitude of daily caloric imbalance that causes obesity. We also cover key aspects of healthy, balanced insulin action in liver, endothelium, brain, and elsewhere. Recent insights into the molecular basis and pathophysiologic harm from SEIRR in these organs are discussed. Importantly, a newly discovered oxide transport chain functions as the master regulator of the balance amongst different limbs of the insulin signaling cascade. This oxide transport chain--abbreviated 'NSAPP' after its five major proteins--fails to function properly during chronic overnutrition, resulting in this harmful pattern of SEIRR. We also review the origins of widespread, chronic overnutrition. Despite its apparent complexity, one factor stands out. A sophisticated junk food industry, aided by subsidies from willing governments, has devoted years of careful effort to promote overeating through the creation of a new class of food and drink that is low- or no-cost to the consumer, convenient, savory, calorically dense, yet weakly satiating. It is past time for the rest of us ...

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Section: Normal Effects Of Central Insulin On the Regulation Of Appetmentioning

confidence: 99%

Imbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forward

Williams

2016

Atherosclerosis

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“…Gpr17 is present in other cell types outside the CNS, including endocrine cells in the gastrointestinal system (H.R., D.A., unpublished observations). The heterogeneity of Gpr17 expression and function might explain the failure to find a food intake or glucose phenotype reported by another group ( 34 ) in global Gpr17 KOs. While this difference may depend on the gene-targeting approach, genetic background, or environmental factors (husbandry, diet, microbiota, experimental design, and calorimetry systems), we think that this is unlikely, based on the fact that in our hands a global Gpr17 KO also causes a distinct metabolic phenotype, which is characterized by a modest reduction of food intake and a substantial increase in energy expenditure, as well as resistance to the effects of high-fat feeding to impair melanocortin signaling (H.R., D.A., unpublished observations).…”

Section: Discussionmentioning

confidence: 91%

Gpr17 in AgRP Neurons Regulates Feeding and Sensitivity to Insulin and Leptin

et al. 2015

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Hypothalamic neurons expressing agouti-related peptide (AgRP) regulate eating and glucose metabolism. Ablation of FOXO1 in AgRP neurons of mice results in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to insulin and leptin. We tentatively identified G-protein–coupled receptor Gpr17 as an effector of FOXO1 orexigenic signals in AgRP neurons. In this study, we generated and characterized AgRP neuron–specific Gpr17 knockout mice (Agrp-Gpr17−/−) to test the hypothesis that Gpr17 regulates appetite, energy expenditure, and metabolism. Agrp-Gpr17−/− mice show reduced food intake, increased relative energy expenditure, and increased satiety, resulting in leanness and reduced body fat. They also show increased central nervous system sensitivity to insulin and leptin and reduced plasma glucose excursions following the administration of glucose or pyruvate. In summary, AgRP neuron–specific Gpr17 knockouts phenocopy FOXO1 knockouts in the same cell type, thus supporting our original hypothesis and providing further impetus to develop Gpr17 antagonists for the treatment of obesity.

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“…Insulin tolerance test (ITT) and oral glucose tolerance test (OGTT) (oGTT) were performed as described (8).…”

Section: Glucose Homeostasis Measurementsmentioning

confidence: 99%

“…MicroCT (CT) measurements were performed using the Quantum FX micro CT preclinical in vivo imaging system (Caliper Life Sciences) as described (8).…”

Section: Body Composition Assessmentsmentioning

confidence: 99%

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Loss of SFRP4 Alters Body Size, Food Intake, and Energy Expenditure in Diet-Induced Obese Male Mice

et al. 2015

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Secreted frizzled-related protein 4 (SFRP4) is an extracellular regulator of the wingless-type mouse mammary tumor virus integration site family (WNT) pathway. SFRP4 has been implicated in adipocyte dysfunction, obesity, insulin resistance, and impaired insulin secretion in patients with type 2 diabetes. However, the exact role of SFRP4 in regulating whole-body metabolism and glucose homeostasis is unknown. We show here that male Sfrp4(-/-) mice have increased spine length and gain more weight when fed a high-fat diet. The body composition and body mass per spine length of diet-induced obese Sfrp4(-/-) mice is similar to wild-type littermates, suggesting that the increase in body weight can be accounted for by their longer body size. The diet-induced obese Sfrp4(-/-) mice have reduced energy expenditure, food intake, and bone mineral density. Sfrp4(-/-) mice have normal glucose and insulin tolerance and β-cell mass. Diet-induced obese Sfrp4(-/-) and control mice show similar impairments of glucose tolerance and a 5-fold compensatory expansion of their β-cell mass. In summary, our data suggest that loss of SFRP4 alters body length and bone mineral density as well as energy expenditure and food intake. However, SFRP4 does not control glucose homeostasis and β-cell mass in mice.

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GPR17 gene disruption does not alter food intake or glucose homeostasis in mice

Cited by 17 publications

References 26 publications

Imbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forward

Imbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forward

Gpr17 in AgRP Neurons Regulates Feeding and Sensitivity to Insulin and Leptin

Loss of SFRP4 Alters Body Size, Food Intake, and Energy Expenditure in Diet-Induced Obese Male Mice

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