Ventromedial hypothalamus–specific Ptpn1 deletion exacerbates diet-induced obesity in female mice
Franck Chiappini, … , Benjamin G. Neel, Barbara B. Kahn
Franck Chiappini, … , Benjamin G. Neel, Barbara B. Kahn
Published August 1, 2014
Citation Information: J Clin Invest. 2014;124(9):3781-3792. https://doi.org/10.1172/JCI68585.
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Research Article Metabolism

Ventromedial hypothalamus–specific Ptpn1 deletion exacerbates diet-induced obesity in female mice

Abstract

Protein-tyrosine phosphatase 1B (PTP1B) regulates food intake (FI) and energy expenditure (EE) by inhibiting leptin signaling in the hypothalamus. In peripheral tissues, PTP1B regulates insulin signaling, but its effects on CNS insulin action are largely unknown. Mice harboring a whole-brain deletion of the gene encoding PTP1B (Ptpn1) are lean, leptin-hypersensitive, and resistant to high fat diet–induced (HFD-induced) obesity. Arcuate proopiomelanocortin (POMC) neuron–specific deletion of Ptpn1 causes a similar, but much milder, phenotype, suggesting that PTP1B also acts in other neurons to regulate metabolism. Steroidogenic factor-1–expressing (SF-1–expressing) neurons in the ventromedial hypothalamus (VMH) play an important role in regulating body weight, FI, and EE. Surprisingly, Ptpn1 deletion in SF-1 neurons caused an age-dependent increase in adiposity in HFD-fed female mice. Although leptin sensitivity was increased and FI was reduced in these mice, they had impaired sympathetic output and decreased EE. Immunohistochemical analysis showed enhanced leptin and insulin signaling in VMH neurons from mice lacking PTP1B in SF-1 neurons. Thus, in the VMH, leptin negatively regulates FI, promoting weight loss, whereas insulin suppresses EE, leading to weight gain. Our results establish a novel role for PTP1B in regulating insulin action in the VMH and suggest that increased insulin responsiveness in SF-1 neurons can overcome leptin hypersensitivity and enhance adiposity.

Authors

Franck Chiappini, Karyn J. Catalano, Jennifer Lee, Odile D. Peroni, Jacqueline Lynch, Abha S. Dhaneshwar, Kerry Wellenstein, Alexandra Sontheimer, Benjamin G. Neel, Barbara B. Kahn

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Figure 7

Increased leptin levels, leptin sensitivity, and leptin signaling in female Sf1-Ptpn1–/– mice on HFD.

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Increased leptin levels, leptin sensitivity, and leptin signaling in fem...
(A) Serum leptin levels at 18 and 28 weeks of age. (B) Leptin mRNA levels (normalized to 18S) in WAT from 28-week-old mice. Controls, n = 21; Sf1-Ptpn1–/–, n = 9. (C) FI (as percentage of baseline) following leptin injections (1.5 mg/kg i.p.) twice a day for 3 days. Baseline FI was measured over the 3 days prior to the experiment, during which mice received saline only. (D) Oxygen consumption (VO2) at baseline and after leptin injection (5 mg/kg i.p.; 3 doses at 12-hour intervals) in fed, 18-week-old mice. n = 8 per genotype. Data represent mean ± SEM. *P < 0.05; **P < 0.01, by unpaired t test (A–C) or paired t test (D). (E) pSTAT3 immunostaining in control (n = 9) and Sf1-Ptpn1–/– (n = 8) mice in the VMH (top) and ARC (bottom). pSTAT3-positive neurons were quantified in 3 to 6 brain slices/mouse. Original magnification, ×10 (upper panels); ×40 (lower panels). Scale bars: 100 μm. *P < 0.05, by unpaired t test. 3V, third ventricle; ME, median eminence. Data represent means ± SEM.