The United States is currently in the midst of an obesity epidemic, a known risk factor for the development of type 2 diabetes, atherosclerotic cardiovascular disease, dyslipidemia, hypertension, and some cancers. There is considerable variation in an individual’s susceptibility to gain weight.  Dr. Christin Carter-Su, Professor of Molecular and Integrative Physiology at the University of Michigan, has identified SH2B1 as a gene that protects against obesity.  Her team has made considerable strides in identifying the role SH2B1 plays in obesity. Recently, her collaborator, S. Farooqi, identified mutations in SH2B1 within her cohort of morbidly obese children. These children exhibit severe early-onset childhood obesity, hyperphagia, and insulin resistance; surprisingly, many also exhibit behavioral abnormalities, including social isolation, learning delay and/or aggressive behavior. By understanding why certain mutations in SH2B1 have such harmful effects, Dr. Carter-Su can identify critical cellular actions of SH2B1 that help protect us from obesity, insulin resistance and behavioral abnormalities. Understanding gained in Dr. Carter-Su’s research can have an immediate effect on society with the potential to identify new therapeutic targets that have never been imagined before!

Dr. Carter-Su’s work strongly suggests that SH2B1 affects cellular motility and the growth and function of neurons. Her goal is to identify novel proteins and functions that are regulated by SH2B1, are critical for the establishment and maintenance of the neural circuits important for normal feeding behavior and energy balance, and can be targeted for therapeutic intervention for obesity, insulin-resistance and/or maladaptive behavior. Her research for the past 30 years has been deeply rooted in understanding biology at the molecular level. This commitment to understanding life at the most fundamental level has allowed Dr. Carter-Su, her collaborators, students, and post-doctoral fellows to make multiple paradigm-shifting discoveries. This focus will accelerate her ability to decipher clues about obesity that lie hidden in the genes of these severely obese individuals.  

Current projects include:

• How Does It Work? Although both human patients with single nucleotide mutations in SH2B1 and mice that lack SH2B1 provide compelling evidence that decreased function of SH2B1 causes severe obesity, insulin resistance and maladaptive behavior, the exact mechanism by which it does so is not known. The Carter-Su team believes that determining exactly how SH2B1 functions in the context of the whole organism and in the context of neurons in the brain will reveal new therapeutic targets for weight control and insulin sensitivity. They seek funds to make and study mouse models in which the human obesity-associated mutations are introduced into SH2B1 in mice. These mice will enable studies not possible in humans to determine how the human mutations disrupt food intake and energy expenditure in those mice as well as the formation and function of neurons in the brain involved in regulating food intake and energy expenditure.
• Therapeutic Targets: The gene for SH2B1 makes multiple forms of SH2B1 that differ only in a small portion of the protein. The different forms of SH2B1 regulate distinct sets of functions in the cell. The Carter-Su lab believes that, in the brain, these differences play a critical role in the formation of the neuronal connections required for regulating body weight. Such a finding would warrant therapeutically targeting particular forms of SH2B1 or critical functions activated by a particular form of SH2B1.