Pioglitazone treatment increases food intake and decreases energy expenditure partially via hypothalamic adiponectin/adipoR1/AMPK pathway

Author(s)

Quaresma, P. G. F. ^[1] ; Reencober, N. ^[2] ; Zanotto, T. M. ^[1] ; Santos, A. C. ^[1] ; Weissmann, L. ^[1] ; de Matos, A. H. B. ^[3] ; Lopes-Cendes, I. ^[3] ; Folli, F. ^{[4, 5]} ; Saad, M. J. A. ^[1] ; Prada, P. O. ^{[2, 1]}

Affiliation

^[1] State Univ Campinas UNICAMP, Dept Internal Med, Campinas, SP - Brazil

^[2] State Univ Campinas UNICAMP, Sch Appl Sci, BR-13484350 Limeira, SP - Brazil

^[3] Univ Campinas UNICAMP, Sch Med Sci, Dept Med Genet, Campinas, SP - Brazil

^[4] Univ Texas Hlth Sci Ctr San Antonio, Div Diabet, Dept Med, San Antonio, TX 78229 - USA

^[5] State Univ Campinas UNICAMP, Departament Med Clin, Obes & Comorbid Res Ctr, Campinas, SP - Brazil

• Document type: Journal article
• Source: International Journal of Obesity; v. 40, n. 1, p. 138-146, JAN 2016.
• Web of Science Citations: 11

Abstract

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. (AU)

• FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
• Grantee: Licio Augusto Velloso
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 12/10338-6 - The regulation of Clk2 and IKK epsilon in the hypothalamus of obese mice
• Grantee: Patrícia de Oliveira Prada
• Support Opportunities: Regular Research Grants