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Central resistin induces hepatic insulin resistance via neuropeptide Y.

ABSTRACT: Sensing of peripheral hormones and nutrients by the hypothalamus plays an important role in maintaining peripheral glucose homeostasis. The hormone resistin impairs the response to insulin in liver and other peripheral tissues. Here we demonstrate that in normal mice resistin delivered in the lateral cerebral ventricle increased endogenous glucose production during hyperinsulinemic-euglycemic clamp, consistent with induction of hepatic insulin resistance. In agreement, central resistin inhibited Akt phosphorylation and increased the expression of glucose-6-phosphatase, the enzyme regulating glucose output in the liver. Central resistin induced expression of proinflammatory cytokines as well as suppressor of cytokine signaling-3, a negative regulator of insulin action in liver. Central infusion of resistin was associated with neuronal activation in the arcuate, paraventricular and dorsomedial nuclei, and increased neuropeptide Y (NPY) expression in the hypothalamus. The effects of central resistin on glucose production as well as hepatic expression of proinflammatory cytokines were abrogated in mice lacking NPY. Pretreatment of wild-type mice with antagonists of the NPY Y1 receptor, but not the Y5 receptor, also prevented the effects of central resistin. Together, these results suggest that resistin action on NPY neurons is an important regulator of hepatic insulin sensitivity.

SUBMITTER: Singhal NS

PROVIDER: S-EPMC6673286 | biostudies-literature | 2007 Nov

REPOSITORIES: biostudies-literature

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Central resistin induces hepatic insulin resistance via neuropeptide Y.

Singhal Neel S NS Lazar Mitchell A MA Ahima Rexford S RS

The Journal of neuroscience : the official journal of the Society for Neuroscience 20071101 47

Sensing of peripheral hormones and nutrients by the hypothalamus plays an important role in maintaining peripheral glucose homeostasis. The hormone resistin impairs the response to insulin in liver and other peripheral tissues. Here we demonstrate that in normal mice resistin delivered in the lateral cerebral ventricle increased endogenous glucose production during hyperinsulinemic-euglycemic clamp, consistent with induction of hepatic insulin resistance. In agreement, central resistin inhibited ...[more]

PMID: 18032666

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Project description:BACKGROUNDWhile saturated fat intake leads to insulin resistance and nonalcoholic fatty liver, Mediterranean-like diets enriched in monounsaturated fatty acids (MUFA) may have beneficial effects. This study examined effects of MUFA on tissue-specific insulin sensitivity and energy metabolism.METHODSA randomized placebo-controlled cross-over study enrolled 16 glucose-tolerant volunteers to receive either oil (OIL, ~1.18 g/kg), rich in MUFA, or vehicle (VCL, water) on 2 occasions. Insulin sensitivity was assessed during preclamp and hyperinsulinemic-euglycemic clamp conditions. Ingestion of 2H2O/acetaminophen was combined with [6,6-2H2]glucose infusion and in vivo 13C/31P/1H/ex vivo 2H-magnet resonance spectroscopy to quantify hepatic glucose and energy fluxes.RESULTSOIL increased plasma triglycerides and oleic acid concentrations by 44% and 66% compared with VCL. Upon OIL intervention, preclamp hepatic and whole-body insulin sensitivity markedly decreased by 28% and 27%, respectively, along with 61% higher rates of hepatic gluconeogenesis and 32% lower rates of net glycogenolysis, while hepatic triglyceride and ATP concentrations did not differ from VCL. During insulin stimulation hepatic and whole-body insulin sensitivity were reduced by 21% and 25%, respectively, after OIL ingestion compared with that in controls.CONCLUSIONA single MUFA-load suffices to induce insulin resistance but affects neither hepatic triglycerides nor energy-rich phosphates. These data indicate that amount of ingested fat, rather than its composition, primarily determines the development of acute insulin resistance.TRIAL REGISTRATIONClinicalTrials.gov NCT01736202.FUNDINGGerman Diabetes Center, German Federal Ministry of Health, Ministry of Culture and Science of the state of North Rhine-Westphalia, German Federal Ministry of Education and Research, German Diabetes Association, German Center for Diabetes Research, Portugal Foundation for Science and Technology, European Regional Development Fund, and Rede Nacional de Ressonancia Magnética Nuclear.

Dataset Information

Central resistin induces hepatic insulin resistance via neuropeptide Y.

Publications

Central resistin induces hepatic insulin resistance via neuropeptide Y.

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