GSE145202: Deletion of brain-specific isoforms of adapter protein SH2B1 protects mice from obesity in a non-leptin-mediated manner

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GROUP CONDITION SAMPLES
Hypothalamus
GSM4308384 GSM4308386 GSM4308388 GSM4308390 GSM4308391 GSM4308392 GSM4308393 GSM4308395 GSM4308399 GSM4308401 GSM4308402 GSM4308403
GSM4308383 GSM4308385 GSM4308387 GSM4308389 GSM4308394 GSM4308396 GSM4308398 GSM4308400
Description

Submission Date: Feb 12, 2020

Summary: Deletion or mutation of SH2B1 (SH2-B, PSM) is associated with severe obesity and insulin resistance in mice and humans. SH2B1 is alternatively spliced into four known isoforms: a, b, g, and d. Contrasting the ubiquitous expression of SH2B1b and g, SH2B1a and d are expressed almost exclusively in brain. Here, we generated mice lacking the brain-specific SH2B1 isoforms (SH2B1adKO mice). SH2B1adKO mice are protected from weight gain on standard and high fat diets, a phenotype caused by hypophagia. SH2B1adKO mice exhibit improvements in glucose homeostasis, yet these are mostly adiposity-dependent. Surprisingly, SH2B1adKO mice demonstrate normal leptin sensitivity. RNA sequencing highlights potential mechanisms underlying the decreased appetite of SH2B1adKO mice including gene expression changes associated with neuronal synapses. These findings suggest that SH2B1a and/or d are key regulators of energy balance. Furthermore, they highlight the profound importance of alternative splicing regulation for body weight.

GEO Accession ID: GSE145202

PMID: 33214137

Description

Submission Date: Feb 12, 2020

Summary: Deletion or mutation of SH2B1 (SH2-B, PSM) is associated with severe obesity and insulin resistance in mice and humans. SH2B1 is alternatively spliced into four known isoforms: a, b, g, and d. Contrasting the ubiquitous expression of SH2B1b and g, SH2B1a and d are expressed almost exclusively in brain. Here, we generated mice lacking the brain-specific SH2B1 isoforms (SH2B1adKO mice). SH2B1adKO mice are protected from weight gain on standard and high fat diets, a phenotype caused by hypophagia. SH2B1adKO mice exhibit improvements in glucose homeostasis, yet these are mostly adiposity-dependent. Surprisingly, SH2B1adKO mice demonstrate normal leptin sensitivity. RNA sequencing highlights potential mechanisms underlying the decreased appetite of SH2B1adKO mice including gene expression changes associated with neuronal synapses. These findings suggest that SH2B1a and/or d are key regulators of energy balance. Furthermore, they highlight the profound importance of alternative splicing regulation for body weight.

GEO Accession ID: GSE145202

PMID: 33214137

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