Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 120, Issue 3, Pages 720-734Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI39620
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Funding
- NIH [R01 DK082417, R01 CA 49152]
- University of Pennsylvania Diabetes Endocrinology Research Center and the Mouse Phenotyping
- Physiology and Metabolism Core [SP30DK019525]
- University of Pennsylvania Research Foundation
- Thomas B. and Jeannette E. Laws McCabe Fund
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Protein tyrosine phosphatase 1B (PTP1B) and SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) have been shown in mice to regulate metabolism via the central nervous system, but the specific neurons mediating these effects are unknown. Here, we have shown that proopiomelanocortin (POMC) neuron-specific deficiency in PTP1B or SHP2 in mice results in reciprocal effects on weight gain, adiposity, and energy balance induced by high-fat diet. Mice with POMC neuron-specific deletion of the gene encoding PTP1B (referred to herein as POMC-Ptp1b(-/-) mice) had reduced adiposity improved leptin sensitivity, and increased energy expenditure compared with wild-type mice, whereas mice with POMC neuron-specific deletion of the gene encoding SHP2 (referred to herein as POMC-Sbp2(-/-) mice) had elevated adiposity, decreased leptin sensitivity, and reduced energy expenditure. POMC-Ptp1b(-/-) mice showed substantially improved glucose homeo-stasis on a high-fat diet, and hyperinsulinemic-euglycemic clamp studies revealed that insulin sensitivity in these mice was improved on a standard chow diet in the absence of any weight difference. In contrast, POMC-Sbp2(-/-) mice displayed impaired glucose tolerance only secondary to their increased weight gain. Interestingly, hypothalamic Pomc mRNA and alpha-melanocyte-stimulating hormone (alpha MSH) peptide levels were markedly reduced in POMC-Sbp2(-/-) mice. These studies implicate PTP1B and SHP2 as important components of POMC neuron regulation of energy balance and point to what we believe to be a novel role for SHP2 in the normal function of the melanocortin system.
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