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Published on: June 3, 2016
Inactivation of hypothalamic FAS protects mice from diet-induced obesity and inflammation
Manu V Chakravarthy1, Yimin Zhu, Li Yin
1Department of Medicine, Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine in St. Louis, MO 63110, USA.
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 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 (TNFalpha) 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.
Insights
Targeting fatty acid synthase (FAS) in the hypothalamus prevents obesity and metabolic disease. This central FAS deficiency improves insulin sensitivity and reduces inflammation, offering a potential strategy for metabolic syndrome.
Area of Science:
- Metabolic disease research
- Neuroendocrinology
- Lipid metabolism
Background:
- Obesity is linked to insulin resistance and chronic inflammation, key components of metabolic syndrome.
- Disrupting lipid synthesis can reduce adiposity, but its systemic effects on metabolic disease propagation are not fully understood.
Purpose of the Study:
- To investigate if inactivating fatty acid synthase (FAS) in the hypothalamus prevents diet-induced obesity and systemic inflammation.
- To determine if central FAS disruption corrects the metabolic disease environment.
Main Methods:
- Mice with hypothalamus-specific FAS inactivation (FASKO) were fed a high-fat diet for 10 weeks.
- Physiological parameters, insulin sensitivity (via hyperinsulinemic-euglycemic clamps), oxidative stress (urinary isoprostanes), and inflammatory responses (TNF-alpha, IL-6) were assessed.
- Pair-feeding studies were conducted to differentiate central effects from reduced adiposity.
Main Results:
- Hypothalamus-specific FAS inactivation protected mice from diet-induced obesity, characterized by hypophagia and hypermetabolism.
- Insulin sensitivity was improved in the liver, with increased Akt signaling, but not in the periphery.
- Reduced urinary isoprostanes indicated less oxidative stress, and blunted TNF-alpha and IL-6 responses suggested reduced systemic inflammation.
Conclusions:
- Central FAS deficiency, specifically in the hypothalamus, is a viable strategy to combat diet-induced obesity and associated metabolic dysfunction.
- The beneficial effects are linked to central mechanisms rather than solely reduced adiposity.
- Targeting central FAS may offer an integrative approach to treating metabolic syndrome by improving hepatic insulin sensitivity and suppressing inflammation.
