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PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice
Ryoichi Banno, … , Wentian Yang, Kendra K. Bence
Ryoichi Banno, … , Wentian Yang, Kendra K. Bence
Published February 15, 2010
Citation Information: J Clin Invest. 2010;120(3):720-734. https://doi.org/10.1172/JCI39620.
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Research Article Metabolism Article has an altmetric score of 5

PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice

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Abstract

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-Shp2–/– mice) had elevated adiposity, decreased leptin sensitivity, and reduced energy expenditure. POMC-Ptp1b–/– mice showed substantially improved glucose homeostasis 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-Shp2–/– mice displayed impaired glucose tolerance only secondary to their increased weight gain. Interestingly, hypothalamic Pomc mRNA and α–melanocyte-stimulating hormone (αMSH) peptide levels were markedly reduced in POMC-Shp2–/– 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.

Authors

Ryoichi Banno, Derek Zimmer, Bart C. De Jonghe, Marybless Atienza, Kimberly Rak, Wentian Yang, Kendra K. Bence

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Figure 1

Generation of mice with POMC neuron deficiency of PTP1B or SHP2.

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POMC-Ptp1b–/– mice are resistant to HFD-induced obesity.
   
(A) Body we...
(A) Deletion efficiency of POMC-Cre as assessed by immunohistochemistry for GFP. Ptp1b+/+;Z/EG control hypothalamus (left) compared with POMC-Ptp1b–/–;Z/EG hypothalamus (right). (B and C) Immunohistochemistry for αMSH was performed in colchicine-injected Ptp1b+/+ or Shp2+/+ controls compared with POMC-Ptp1b–/– or -Shp2–/– mice. 3V, third ventricle. Scale bars: 50 μm. (D) Quantification of POMC cell number and cell size in hypothalamic sections of Ptp1b+/+ and Shp2+/+ (WT) compared with POMC-Ptp1b–/– and POMC-Shp2–/– (KO) mice; adult (3–8 months old) mice were analyzed, n = 3 mice per genotype, 2–4 sections per mouse. (E) Detection of deletion of Ptp1b or Shp2 alleles (Δ) in POMC-Ptp1b–/– and -Shp2–/– mice compared with Ptp1b+/+ and Shp2+/+ controls. DNA was extracted from different tissues (P, pituitary; H, hypothalamus; B, whole brain; L, liver; K, kidney; F, fat; M, skeletal muscle; and hindbrain), and deletion of the floxed allele was detected by PCR. Recombination was detected only in pituitary, hypothalamus, whole brain, and hindbrain of POMC-Ptp1b–/– and -Shp2–/– mice. A PCR reaction with IL-2 was used as an internal control. (F) PTP1B protein levels in Ptp1b+/+ controls compared with POMC-Ptp1b–/– mice (top panels) and SHP2 protein levels in Shp2+/+ controls compared with POMC-Shp2–/– mice (bottom panels) as determined by immunoblotting. SHP2 and ERK2 protein levels, respectively, are shown as a loading control. Hypo, hypothalamus.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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