OR12-6 Deletion Of The Brain-Specific α And δ Isoforms Of SH2B1 Protects Against Diet-Induced Obesity In A Leptin-Independent Manner

Abstract

Abstract The scaffold protein SH2B1 plays a critical role in the regulation of energy balance and glucose homeostasis—humans with mutations in SH2B1 are obese and diabetic, as are SH2B1KO mice. The 4 known isoforms of SH2B1 (α, β, γ, δ), which differ only in their C-terminal tails, have distinct expression profiles: β and γ are ubiquitously expressed whereas α and δ are expressed almost exclusively in brain. Some human obesity-associated mutations of SH2B1 are specific to the α and δ isoforms. However, the contributions of the latter isoforms to the regulation of energy balance are not understood. Knowing that the brain is a major coordinator of energy homeostasis, we hypothesized that the brain-specific α and δ isoforms of SH2B1 would be critical players in the regulation of energy balance. To investigate the potential contribution of these isoforms to the control of energy balance, we used CRISPR-Cas9 to delete SH2B1 α and δ in mice (SH2B1αδKO). On a standard chow diet, SH2B1αδKO mice exhibit decreased body weight, fat content, and circulating leptin levels, as well as increased lean content for their body weight. They are hypophagic yet have normal energy expenditure, suggesting that their decreased body weight and fat mass result from reduced food intake. To determine whether deletion of these isoforms could protect against extreme weight gain, we challenged SH2B1αδKO mice with a 60% high fat diet. SH2B1αδKO mice are protected against the high fat diet: compared to WT littermates, they weigh less, have decreased fat mass and leptin levels, are leaner for their body weight, and are protected against impairments to glucose control. Because SH2B1 is recruited to the activated leptin receptor/JAK2 complex, we tested whether deletion of the α and δ isoforms of SH2B1 enhance leptin sensitivity. SH2B1αδKO mice exhibit normal expression levels of hypothalamic genes that are associated with leptin-dependent regulation of feeding behavior, as well as normal sensitivity to leptin in vivo. Together these data suggest that the α and/or δ isoforms of SH2B1, acting in a leptin-independent manner, are potent regulators of energy balance. To explain the lean phenotype of SH2B1αδKO mice, we considered the unique actions of these isoforms. At the cellular level, the β, γ, and δ isoforms enhance neurite outgrowth and/or neurotrophic factor-dependent gene expression in neuron-like PC12 cells. In contrast, SH2B1α does not enhance these actions, and even inhibits the ability of SH2B1β to enhance these activities. We propose that the removal of SH2B1α in SH2B1αδKO mice enables the remaining β and/or γ isoforms to enhance the function of neurons that contribute to the regulation of energy balance, as they are now free from SH2B1α’s inhibitory influence. Funding: NIH R01, NSF Graduate Research Fellowship