期刊
JOURNAL OF LIPID RESEARCH
卷 50, 期 4, 页码 630-640出版社
ELSEVIER
DOI: 10.1194/jlr.M800379-JLR200
关键词
metabolic syndrome; insulin resistance; type 2 diabetes mellitus
资金
- American Diabetes Association [1-07-JF-12]
- Mentor-Based Postdoctoral Fellowship Award
- National Institutes of Health [DK076729, P50 HL083762]
- Clinical Nutrition Research Unit [DK56341]
- Diabetes Research and Training Center [DK20579]
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 beta cells protected them from diet-induced obesity. Though high-fat fed FASKO mice had no beta-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 (TNF alpha) 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.-Chakravarthy, M. V., Y. Zhu, L. Yin, T. Coleman, K. L. Pappan, C. A. Marshall, M. L. McDaniel, and C. F. Semenkovich. Inactivation of hypothalamic FAS protects mice from diet-induced obesity and inflammation. J. Lipid Res. 2009. 50: 630-640.
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