A role for fatty acid metabolism in the regulation of energy balance has been considered only recently, and generated the hypothesis that pharmacological alteration of fatty acid flux might affect food intake. Among the enzymes that facilitate fatty acid synthesis, utilization, and degradation, our working group has focused on three candidates as targets for obesity intervention. Fatty acid synthase (FAS) is a lipogenic enzyme that catalyzes the condensation of acetyl-CoA and malonyl-CoA to generate long-chain fatty acids. Carnitine palmitoyl-transferase-1 (CPT-1) is pace-setting enzyme for the entry of fatty acids into mitochondria for oxidation. Glycerol-3-phosphate acyltransferase (GPAT) controls the rate-limiting step in triglyceride synthesis. We have examined the effects of small molecules that modulate fatty acid metabolic flux on food intake, peripheral metabolism, and glucose tolerance. When administered centrally or peripherally, they reduce food intake and cause profound and reversible weight loss. In diet-induced obese mouse models, glucose tolerance is improved, and inflammatory cytokines are reduced. We hypothesize that that mechanisms of these effects are multiple. One mechanism may involve AMP-activated protein kinase (AMPK), a known peripheral energy-sensing kinase. Collectively, these data suggest a role for fatty acid metabolism in the perception and regulation of energy balance, and as possible targets for treatment of metabolic syndrome.
Research Activities :
Honors and Awards :
- 1992: McKnight Scholars Award in Neuroscience
- 2000: Shannon Award from NIH 2004 Women’s Leadership Group for the Johns Hopkins University
- 2004: Dean’s Lecture for the School of Medicine 2006 Johns Hopkins University Leadership Program