Role of Shp2 in forebrain neurons in regulating metabolic and cardiovascular functions and responses to leptin
Open accessAbstract
Objective We examined whether deficiency of Src homology 2 containing phosphatase (Shp2) signaling in forebrain neurons alters metabolic and cardiovascular regulation under various conditions and if it attenuates the anorexic and cardiovascular effects of leptin. We also tested whether forebrain Shp2 deficiency alters blood pressure (BP) and heart rate (HR) responses to acute stress.Design Forebrain Shp2(-/-) mice were generated by crossing Shp2(flox/flox) mice with CamKIIα-cre mice. At 22-24 weeks of age, the mice were instrumented for telemetry for measurement of BP, HR and body temperature (BT). Oxygen consumption (VO2), energy expenditure and motor activity were monitored by indirect calorimetry.Results Shp2/CamKIIα-cre mice were heavier (46±3 vs 32±1 g), hyperglycemic, hyperleptinemic, hyperinsulinemic and hyperphagic compared to Shp2(flox/flox) control mice. Shp2/CamKIIα-cre mice exhibited reduced food intake responses to fasting/refeeding and impaired regulation of BT when exposed to 15 and 30 °C ambient temperatures. Despite being obese and having many features of metabolic syndrome, Shp2/CamKIIα-cre mice had similar daily average BP and HR compared to Shp2(flox/flox) mice (112±2 vs 113±1 mm Hg and 595±34 vs 650±40 b.p.m.), but exhibited increased BP and HR responses to cold exposure and acute air-jet stress test. Leptin's ability to reduce food intake and to raise BP were markedly attenuated in Shp2/CamKIIα-cre mice.Conclusion These results suggest that forebrain Shp2 signaling regulates food intake, appetite responses to caloric deprivation and thermogenic control of body temperature during variations in ambient temperature. Deficiency of Shp2 signaling in the forebrain is associated with augmented cardiovascular responses to cold and acute stress but attenuated BP responses to leptin.
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Targeted deletion of SHP2 in the forebrain or in POMC neurons markedly attenuated increases in blood pressure and lowering of glucose levels in response to chronic leptin infusion, indicating an important role for SHP2 signalling in these cardiometabolic functions.
“Moreover, targeted deletion of SHP2 in the forebrain or in POMC neurons markedly attenuated increases in BP and lowering of glucose levels in response to chronic leptin infusion, indicating an important role for SHP2 signalling in these cardiometabolic functions146,147.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [147]
SHP2 signaling may contribute to the effects of leptin on SNS activity and BP.
“Also, the chronic BP effects of leptin were attenuated in mice with forebrain SHP2 deletion110 suggesting that SHP2 signaling may contribute to the effects of leptin on SNS activity and BP.”
From Obesity-Induced Hypertension: Interaction of Neurohumoral and Renal Mechanisms (2015) · cites this paper as [110]
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- Authors
- do Carmo, J. M., da Silva, A. A., Sessums, P. O., Ebaady, S. H., Pace, B. R., Rushing, J. S., Davis, M. T., & Hall, J. E.
- Affiliations
- University of Mississippi Medical Center (US)
- Venue
- International Journal of Obesity
- Published
- 2013-09-13
- Volume
- 38
- Issue
- 6
- Pages
- 775-783
- ISSN
- 0307-0565 (ISSN-L)
- 1476-5497
- PMC
- PMC3954949
- OpenAlex
- W2012782405
- Cited by
- 26
- References
- 21
- Citations by year
- 2026: 1 · 2024: 3 · 2022: 2 · 2021: 1 · 2020: 3 · 2019: 3 · 2018: 2 · 2017: 1 · 2016: 3 · 2015: 4 · 2014: 3
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- International Journal of Obesity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association
- National Heart, Lung, and Blood Institute (P01-HL-51971, P01HL051971)
- National Institute of General Medical Sciences (P20GM104357)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- SHP2, forebrain neurons, leptin, food intake regulation, obesity, metabolic syndrome, blood pressure, heart rate, cold stress response, acute stress response, thermoregulation, thermogenesis, energy expenditure, hyperphagia, hyperinsulinemia, hyperleptinemia, cardiovascular regulation
- MeSH terms
- Animals, Blood Pressure, Body Temperature, Calorimetry, Indirect, Eating, Energy Metabolism, Heart Rate, Male, Mice, Transgenic, Neurons, Obesity, Oxygen Consumption, Signal Transduction, Prosencephalon, Leptin, Intracellular Signaling Peptides and Proteins, Mice, Receptors, Leptin, Protein Tyrosine Phosphatase, Non-Receptor Type 11
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