Deletion of the Brain-Specific α and δ Isoforms of Adapter Protein SH2B1 Protects Mice From Obesity
Jessica L Cote1, Lawrence S Argetsinger2, Anabel Flores3
1Neuroscience Program, University of Michigan Medical School, Ann Arbor, MI.
Abstract:
Mice lacking SH2B1 and humans with variants of SH2B1 display severe obesity and insulin resistance. SH2B1 is an adapter protein that is recruited to the receptors of multiple hormones and neurotrophic factors. Of the four known alternatively spliced SH2B1 isoforms, SH2B1β and SH2B1γ exhibit ubiquitous expression, whereas SH2B1α and SH2B1δ are essentially restricted to the brain. To understand the roles for SH2B1α and SH2B1δ in energy balance and glucose metabolism, we generated mice lacking these brain-specific isoforms (αδ knockout [αδKO] mice). αδKO mice exhibit decreased food intake, protection from weight gain on standard and high-fat diets, and an adiposity-dependent improvement in glucose homeostasis. SH2B1 has been suggested to impact energy balance via the modulation of leptin action. However, αδKO mice exhibit leptin sensitivity that is similar to that of wild-type mice by multiple measures. Thus, decreasing the abundance of SH2B1α and/or SH2B1δ relative to the other SH2B1 isoforms likely shifts energy balance toward a lean phenotype via a primarily leptin-independent mechanism. Our findings suggest that the different alternatively spliced isoforms of SH2B1 perform different functions in vivo.
Insights
Mice lacking brain-specific SH2B1 isoforms (SH2B1α and SH2B1δ) reduce food intake and weight gain, improving glucose metabolism independently of leptin. This suggests distinct functions for SH2B1 isoforms in energy balance.
Area of Science:
- Molecular Biology
- Neuroendocrinology
- Metabolic Research
Background:
- SH2B1 (SH2 domain-containing adaptor protein 1) is crucial for regulating energy balance and insulin sensitivity.
- SH2B1 has four known alternatively spliced isoforms, with SH2B1α and SH2B1δ predominantly expressed in the brain.
Purpose of the Study:
- To investigate the specific roles of brain-specific SH2B1 isoforms (SH2B1α and SH2B1δ) in energy homeostasis and glucose metabolism.
- To determine if the effects of SH2B1 on energy balance are mediated by leptin signaling.
Main Methods:
- Generation of mice lacking brain-specific SH2B1 isoforms (SH2B1α/δ knockout [αδKO] mice).
- Assessment of food intake, body weight, adiposity, and glucose homeostasis in αδKO and wild-type mice.
- Evaluation of leptin sensitivity in αδKO mice.
Main Results:
- αδKO mice exhibited reduced food intake and protection against weight gain on both standard and high-fat diets.
- Glucose homeostasis was improved in an adiposity-dependent manner in αδKO mice.
- Leptin sensitivity in αδKO mice was comparable to wild-type mice, indicating a leptin-independent mechanism.
Conclusions:
- The brain-specific SH2B1 isoforms (SH2B1α and SH2B1δ) play a significant role in regulating energy balance and adiposity.
- Reduced expression of SH2B1α and/or SH2B1δ promotes a lean phenotype through a mechanism largely independent of leptin signaling.
- Different SH2B1 isoforms likely possess distinct in vivo functions, contributing to the complexity of metabolic regulation.
