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Pioglitazone Treatment Increases Food Intake And Decreases Energy Expenditure Partially Via Hypothalamic Adiponectin/adipor1/ampk Pathway

By Quaresma, P. G. F., N., T. M., A. C., L., A. H. B., I., F., M. J. A. and P. O.

Abstract

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)INTRODUCTION: Thiazolidinediones (TZDs) enhanced body weight (BW) partially by increased adipogenesis and hyperphagia. Neuronal PPAR. knockout mice on high-fat diet (HFD) are leaner because of enhanced leptin response, although it could be secondary to their leanness. Thus, it still is an open question how TZDs may alter energy balance. Multiple factors regulate food intake (FI) and energy expenditure (EE), including anorexigenic hormones as insulin and leptin. Nonetheless, elevated hypothalamic AMPK activity increases FI and TZDs increase AMPK activity in muscle cells. Thus, the aim of the present study was to investigate whether Pioglitazone (PIO) treatment alters hypothalamic insulin and leptin action/signaling, AMPK phosphorylation, and whether these alterations may be implicated in the regulation of FI and EE. METHODS: Swiss mice on HFD (2 months) received PIO (25 mg kg(-1) per day-gavage) or vehicle for 14 days. AMPK and AdipoR1 were inhibited via Intracerebroventricular injections using Compound C (CompC) and small interference RNA (siRNA), respectively. Western blot, real-time PCR and CLAMS were done. RESULTS: PIO treatment increased BW, adiposity, FI, NPY mRNA and decreased POMC mRNA expression and EE in HFD mice. Despite higher adiposity, PIO treatment improved insulin sensitivity, glucose tolerance, decreased insulin and increased adiponectin serum levels. This result was associated with, improved insulin and leptin action/signaling, decreased alpha 2AMPK(Ser491) phosphorylation and elevated Acetyl-CoA carboxylase and AMPK(Thr172) phosphorylation in hypothalamus. The inhibition of hypothalamic AMPK with CompC was associated with decreased adiposity, FI, NPY mRNA and EE in PIO-treated mice. The reduced expression of hypothalamic AdipoR1 with siRNA concomitantly with PIO treatment reverted PIO induced obesity development, suggesting that adiponectin may be involved in this effect. CONCLUSIONS: These results demonstrated that PIO, despite improving insulin/leptin action in hypothalamus, increases FI and decreases EE, partially, by activating hypothalamic adiponectin/AdipoR1/AMPK axis. Suggesting a novel mechanism in the hypothalamus by which TZDs increase BW.401138146Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)INCT (Instituto Nacional Ciencia e Tecnologia de Obesidade e Diabetes) [573856/2008-7]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP [Auxilio Regular 2012/10338-6, CEPID 2013/07607-8]CNPq [573856/2008-7, UNIVERSAL 481084/2013-4

Topics: Activated Protein-kinase, Type-2 Diabetes-mellitus, Ppar-gamma, Adiponectin Receptors, Insulin-resistance, Neuropeptide-y, Glucose-metabolism, Amp-kinase, Obesity, Leptin
Publisher: LONDON
Year: 2016
DOI identifier: 10.1038/ijo.2015.134
OAI identifier: oai:repositorio.unicamp.br:REPOSIP/241697
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