The central administration of C75, a fatty acid synthase inhibitor, activates sympathetic outflow and thermogenesis in interscapular brown adipose tissue
The present work investigated the participation of interscapular brown adipose tissue (IBAT), which is an important site for thermogenesis, in the anti-obesity effects of C75, a synthetic inhibitor of fatty acid synthase (FAS). We report that a single intracerebroventricular (i.c.v.) injection of C75 induced hypophagia and weight loss in fasted male Wistar rats. Furthermore, C75 induced a rapid increase in core body temperature and an increase in heat dissipation. In parallel, C75 stimulated IBAT thermogenesis, which was evidenced by a marked increase in the IBAT temperature that preceded the rise in the core body temperature and an increase in the mRNA levels of uncoupling protein-1. As with C75, an i.c.v. injection of cerulenin, a natural FAS inhibitor, increased the core body and IBAT temperatures. The sympathetic IBAT denervation attenuated all of the thermoregulatory effects of FAS inhibitors as well as the C75 effect on weight loss and hypophagia. C75 induced the expression of Fos in the paraventricular nucleus, preoptic area, dorsomedial nucleus, ventromedial nucleus, and raphé pallidus, all of which support a central role of FAS in regulating IBAT thermogenesis. These data indicate a role for IBAT in the increase in body temperature and hypophagia that is induced by FAS inhibitors and suggest new mechanisms explaining the weight loss induced by these compounds.
KeywordsBrown adipose tissue Fatty acid synthase inhibitors Thermogenesis Sympathetic activation
We thank José Roberto da Silva (Laboratory of Endocrinology; HCFMRP-USP) for the determination of plasma corticosterone, and Dr. Léa Maria Zanini Maciel and Giselle Aparecida Caixe de Carvalho Paixão (Laboratory of Thyroid and Neonatal Screening; HCFMRP-USP) for the determination of plasma total thyroxine. We are also indebted to Elza Aparecida Filippin, Neusa Maria Zanon, Lilian Zorzenon Carmo de Paula, Maria Valci Aparecida dos Santos, and Victor Diaz Galban for their technical assistance. This work was supported by grants from the Fundação de Amparoà Pesquisa do Estado de São Paulo (Fapesp 08/06694–6, 09/07584–2, 10/11083–6, and 10/11015–0) and from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 140094/07–5, 306101/09–2, 303786/08–6, and 305149/12–1).
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