# Cellular and Molecular Mechanisms of SH2B1 Mutations That Cause Profound Childhood Obesity

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $454,156

## Abstract

ABSTRACT
Obesity is a major health problem associated with a significant increase in metabolic syndrome, diabetes, and
heart disease. Thus, obesity demands an in-depth understanding of its causes at the cellular, molecular and
organismal level. In an exciting new development, identification of human mutations in SH2B1 that associate
with profound childhood obesity implicate the scaffold protein SH2B1 as a critical regulator of body weight, in-
sulin sensitivity and behavior. There is a fundamental gap in our understanding of how SH2B1 regulates neural
circuitry that maintains energy homeostasis and how human obesity mutations in SH2B1 disrupt that circuitry
and contribute to obesity. Our long-term goal is to identify novel key signaling proteins and/or gene regulatory
events that are regulated by SH2B1, critical for establishing and maintaining neural circuits important for nor-
mal feeding behavior and energy balance, can be targeted for therapeutic intervention for obesity, insulin-
resistance and/or maladaptive behavior. Primary neurons, novel mouse models and cultured cells will be used
to test the central hypothesis that SH2B1 is crucial for the establishment and maintenance of neural circuits
important for normal feeding behavior and energy balance. Mechanistically, SH2B1 serves as a scaffold pro-
tein that enhances signaling pathways at the plasma membrane and cycles to the nucleus, both are required
for regulating gene transcription and neurite outgrowth. Human disease mutations impair a subset of these re-
sponses. The specific aims are: 1) Determine neurotrophic ligand signaling pathways regulated by SH2B1 and
impaired by the human mutations; 2) Determine how nuclear SH2B1, which is required for neurite outgrowth,
enhances gene expression and the human mutations impair that enhancement; and 3) Define the role for
SH2B1 in neural circuit formation and transcription in hypothalamic neurons implicated in energy balance. This
research is innovative because: 1) SH2B1 was recently implicated as a human obesity gene; 2) newly identi-
fied SH2B1 mutations provide powerful tools to study the causes of obesity; 3) the concept of coordinating an
integrated response to neurotrophic ligands by movement of scaffold proteins between the plasma membrane
and the nucleus is novel; and 4) many of the proposed techniques and mouse models are cutting edge, includ-
ing CRISPR/Cas9 technology to delete or edit Sh2b1, mouse models to study the effect of SH2B1 on neuronal
projections, studying gene expression within the small population of LepRb neurons in the hypothalamus, and
the unique Sh2b1P322S mouse that enables study of the impact of a human SH2B1 mutation in intact mice and
isolated neurons. The proposed research is significant because it will provide critical insight into the cellular
and molecular mechanisms by which SH2B1 and the human mutations affect the function of neurons, including
those that regulate body weight, and how complex, multi-protein ...

## Key facts

- **NIH application ID:** 9923644
- **Project number:** 5R01DK107730-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** CHRISTIN CARTER-SU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $454,156
- **Award type:** 5
- **Project period:** 2016-07-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923644

## Citation

> US National Institutes of Health, RePORTER application 9923644, Cellular and Molecular Mechanisms of SH2B1 Mutations That Cause Profound Childhood Obesity (5R01DK107730-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9923644. Licensed CC0.

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