Inactivation of hypothalamic FAS protects mice from diet-induced obesity and inflammation

Manu V. Chakravarthy, Yimin Zhu, Li Yin, Trey Coleman, Kirk L. Pappan, Connie A. Marshall, Michael L. McDaniel, Clay F. Semenkovich

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Obesity promotes insulin resistance and chronic inflammation. Disrupting any of several distinct steps in lipid synthesis decreases adiposity, but it is unclear if this approach coordinately corrects the environment that propagates metabolic disease. We tested the hypothesis that inactivation of FAS in the hypothalamus prevents diet-induced obesity and systemic inflammation. Ten weeks of high-fat feeding to mice with inactivation of FAS (FASKO) limited to the hypothalamus and pancreatic β cells protected them from diet-induced obesity. Though high-fat fed FASKO mice had no β-cell phenotype, they were hypophagic and hypermetabolic, and they had increased insulin sensitivity at the liver but not the periphery as demonstrated by hyperinsulinemic-euglycemic clamps, and biochemically by increased phosphorylated Akt, glycogen synthase kinase-3beta, and FOXO1 compared with wild-type mice. High-fat fed FASKO mice had decreased excretion of urinary isoprostanes, suggesting less oxidative stress and blunted tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) responses to endotoxin, suggesting less systemic inflammation. Pair-feeding studies demonstrated that these beneficial effects were dependent on central FAS disruption and not merely a consequence of decreased adiposity. Thus, inducing central FAS deficiency may be a valuable integrative strategy for treating several components of the metabolic syndrome, in part by correcting hepatic insulin resistance and suppressing inflammation.

Original languageEnglish
Pages (from-to)630-640
Number of pages11
JournalJournal of lipid research
Volume50
Issue number4
DOIs
StatePublished - Mar 2009

Keywords

  • Insulin resistance
  • Metabolic syndrome
  • Type 2 diabetes mellitus

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