Research

The United States is currently in the midst of an epidemic of obesity, a 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, and this variation stems from genetic and environmental influences. Our lab is interested in genetic components that increase or decrease sensitivity to weight gain.

More specifically, we are currently working to understand how the SH2B1 gene protects against obesity. Our collaborator, I. Sadaf Farooqi, has identified mutations in SH2B1 within her cohort of morbidly obese children. Some of the children with these mutations weigh over 220 pounds by the time they are 12 years old! These children overeat and are insulin resistant. 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, we can identify critical cellular actions of SH2B1 that help protect people from obesity, insulin resistance, and behavioral abnormalities.

Our lab’s work strongly suggests that SH2B1 affects cellular motility and the growth and function of neurons. Our goal is to identify novel proteins and cellular functions that are regulated by SH2B1, are critical for the establishment and maintenance of neural circuits important for normal feeding behavior and energy use, and can be targeted for therapeutic intervention for obesity, insulin resistance, and/or maladaptive behavior. Read more about our current projects below.

Human patients with single nucleotide mutations in SH2B1, along with mice that lack SH2B1, provide compelling evidence that disrupted function of SH2B1 causes severe obesity, insulin resistance, and maladaptive behavior. However, the exact mechanism by which mutations in, or the complete absence of, SH2B1 lead to these changes is not known. We believe that determining exactly how SH2B1 functions in the context of the whole organism, as well as within neurons that regulate feeding behavior and energy use, will reveal new therapeutic targets for weight control and insulin sensitivity. We are using genetically engineered mouse models in which the human obesity-associated mutations are introduced into SH2B1 in mice. These mice enable us to study how mutations in SH2B1 disrupt food intake and energy expenditure, and provide insight into how the SH2B1 gene functions throughout the whole organism and within neurons important for the regulation of appetite, body weight, and energy consumption.

The gene for SH2B1 makes multiple forms of the SH2B1 protein that differ only in a small portion of the protein. The different versions of SH2B1 regulate distinct sets of functions in the cell. We believe that, in the brain, the differences in forms of SH2B1 play a critical role in the function of neuronal connections required for regulating body weight. We are using genetically engineered mouse models to identify the contribution of each form of SH2B1 to the regulation of feeding behavior, energy use, and other aspects of metabolism. We are also using cultured cells to investigate on a much smaller scale exactly where and how each form of SH2B1 acts within individual cells. New information about the role of distinct forms of SH2B1 would warrant therapeutically targeting a particular form, or critical functions activated by a particular form, of SH2B1.