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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

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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 1

Selective ablation of PTP1B expression in SF-1 neurons of VMH of Sf1-Cre Ptpn1flox/flox lsl-tdTomato mice.

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Selective ablation of PTP1B expression in SF-1 neurons of VMH of Sf1-Cre...
Coronal sections of hypothalami from Sf1-Cre Ptpn1flox/flox lsl-tdTomato mice showing PTP1B (green) and tdTomato (red) expression in VMH and LH neurons. The tdTomato reporter marks SF-1 neurons in the VMH only. (A–J) Note that PTP1B is still present in tdTomato-negative LH neurons. (K–T) PTP1B protein is selectively absent in tdTomato-positive SF-1 neurons of the VMH. (P–T) Same sections at greater magnification. All immunofluorescence images are from the same brain. A, F, K, and P show cell nuclei stained with DAPI. Merged 1 shows overlay of anti-PTP1B (green) and tdTomato (red) fluorescence. Merged 2 shows overlay of DAPI, anti-PTP1B (green), and tdTomato (red) staining. Scale bars: 100 μm (A–E, K–O); 20 μm (F–J, P–T). Original magnification: ×10 (A–E, K–O); ×63 (F–J, P–T).
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