Principal Investigator:  Bassil M. Kublaoui, M.D., Ph.D.
Bibliography

The Kublaoui Lab studies the neuroendocrine regulation of energy balance and works closely with the laboratory of Dr. Andrew Zinn. Obesity in both adults and children is an epidemic with 65% of U.S. adults and 25% of children being overweight or obese. This project began with the identification of a novel form of monogenic obesity in a child with a balanced translocation disrupting a gene called SIM1. The Sim1 heterozygous knock out mouse is also hyperphagic, obese and sensitive to high fat. Sim1 is expressed in the hypothalamus, mostly in the paraventricular nucleus. Our objectives are to define the molecular function of SIM1 in the regulation of food intake as it relates to known hypothalamic pathways. Sim1 heterozygous mice have the phenotypic constellation suggested to be a hallmark of defective melanocortin signaling, namely hyperphagia, obesity, increased length, and a sensitivity to high fat. This constellation is not only found in melanocortin-4 receptor-/- (mc4r-/-) mice and Agouti Yellow mice (Ay) but also in mice deficient in bdnf (brain derived neurotrophic factor) and its receptor. We showed that unlike mc4r-/- mice, Sim1 heterozygotes have normal energy expenditure. We also showed that Sim1 heterozygotes are resistant to the anorectic effect of MTII (an Mc4r agonist), but not its effect of energy expenditure and that Sim1 heterozygotes fail to activate PVN neurons in response to MTII. This shows that Sim1 is necessary for proper melanocortin signaling in the PVN. Current projects in the lab aim to define the neuroanatomical pathways important for Sim1 regulation of food intake, signal transduction pathways that interact with Sim1 function, and downstream targets of Sim1 action as a transcription factor.