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SH2B1 regulation of energy balance, body weight, and glucose metabolism.

ABSTRACT: The Src homology 2B (SH2B) family members (SH2B1, SH2B2 and SH2B3) are adaptor signaling proteins containing characteristic SH2 and PH domains. SH2B1 (also called SH2-B and PSM) and SH2B2 (also called APS) are able to form homo- or hetero-dimers via their N-terminal dimerization domains. Their C-terminal SH2 domains bind to tyrosyl phosphorylated proteins, including Janus kinase 2 (JAK2), TrkA, insulin receptors, insulin-like growth factor-1 receptors, insulin receptor substrate-1 (IRS1), and IRS2. SH2B1 enhances leptin signaling by both stimulating JAK2 activity and assembling a JAK2/IRS1/2 signaling complex. SH2B1 promotes insulin signaling by both enhancing insulin receptor catalytic activity and protecting against dephosphorylation of IRS proteins. Accordingly, genetic deletion of SH2B1 results in severe leptin resistance, insulin resistance, hyperphagia, obesity, and type 2 diabetes in mice. Neuron-specific overexpression of SH2B1β transgenes protects against diet-induced obesity and insulin resistance. SH2B1 in pancreatic β cells promotes β cell expansion and insulin secretion to counteract insulin resistance in obesity. Moreover, numerous SH2B1 mutations are genetically linked to leptin resistance, insulin resistance, obesity, and type 2 diabetes in humans. Unlike SH2B1, SH2B2 and SH2B3 are not required for the maintenance of normal energy and glucose homeostasis. The metabolic function of the SH2B family is conserved from insects to humans.

SUBMITTER: Rui L

PROVIDER: S-EPMC4127586 | biostudies-other | 2014 Aug

REPOSITORIES: biostudies-other

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SH2B1 regulation of energy balance, body weight, and glucose metabolism.

Rui Liangyou L

World journal of diabetes 20140801 4

The Src homology 2B (SH2B) family members (SH2B1, SH2B2 and SH2B3) are adaptor signaling proteins containing characteristic SH2 and PH domains. SH2B1 (also called SH2-B and PSM) and SH2B2 (also called APS) are able to form homo- or hetero-dimers via their N-terminal dimerization domains. Their C-terminal SH2 domains bind to tyrosyl phosphorylated proteins, including Janus kinase 2 (JAK2), TrkA, insulin receptors, insulin-like growth factor-1 receptors, insulin receptor substrate-1 (IRS1), and IR ...[more]

PMID: 25126397

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Project description:Experimentally establishing a group's body weight maintenance energy requirement is an important component of metabolism research. At present, the reference approach for measuring the metabolizable energy intake (MEI) from foods required for body weight maintenance in non-confined subjects is the doubly-labeled water (DLW)-total energy expenditure (TEE) method. In the current study, we evaluated an energy-intake weight balance method as an alternative to DLW that is more flexible and practical to apply in some settings.The hypothesis was tested that MEI from foods observed in a group of subjects maintaining a constant energy intake while keeping their weight within ±1 kg over 10 days is non-significantly different from DLW-measured TEE (TEEDLW). Six non-obese subjects evaluated as part of an earlier study completed the inpatient protocol that included a 3-day initial adjustment period.The group body weight coefficient of variation (X ± SD) during the 10-day balance period was 0.38 ± 0.10% and the slope of the regression line for body weight versus protocol day was non-significant at 1.8 g/day (R2, 0.002, p = 0.98). MEI from foods observed during the 10-day balance period (2390 ± 543 kcal/day) was non-significantly different (p = 0.96) from TEE measured by DLW (2373 ± 713 kcal/day); the MEI/TEEDLW ratio was 1.03 ± 0.15 (range 0.87-1.27) and the correlation between MEI from foods and TEEDLW was highly significant (R2, 0.88, p = 0.005).A carefully managed 10-day protocol that includes a constant MEI level from foods with weight stability (±1 kg) will provide a group's body weight maintenance energy requirement similar to that obtained with DLW. This approach opens the possibility of conducting affordable weight balance studies, shorter in duration than those previously reported, that are needed to answer a wide range of questions in clinical nutrition. Trial registration The study is registered at http://www.clinicaltrials.gov (NCT01672632; August 20, 2012).

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SH2B1 regulation of energy balance, body weight, and glucose metabolism.

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SH2B1 regulation of energy balance, body weight, and glucose metabolism.

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