PTP1B: A molecular mediator of leptin resistance.

Abstract

Leptin acts in the brain to suppress food intake and body adiposity, but in most cases obesity is associated with a resistance to leptin action. Protein tyrosine phosphatase 1B (PTP1B) dephosphorylates key components of the leptin receptor signaling cascade, and represents a molecular mediator of leptin resistance. Our recent work demonstrates that hypothalamic PTP1B levels are elevated in a model of aging-induced leptin resistance, and that acute inhibition of PTP1B improves hypothalamic leptin sensitivity in this setting. We therefore tested whether hypothalamic PTP1B is increased in diet-induced obesity, another model of leptin resistance. Twenty-eight days of high-fat (HF) feeding increased body weight and fat pad weights ( P <0.05) compared to low-fat (LF), and also increased PTP1B protein levels in the mediobasal hypothalamus ( P =0.003). To define a mechanism underlying this HF-induced increase in PTP1B, the independent effects of hyperleptinemia and exposure to a high-fat diet were tested. Leptin-deficient ob/ob mice were fed LF or HF diets and treated with leptin or saline for 14 days. Leptin treatment increased hypothalamic PTP1B in the LF mice ( P =0.003), but had no effect in HF mice. However, HF mice exhibited a marked increase in hypothalamic PTP1B mRNA irrespective of leptin treatment ( P <0.001). These data are consistent with the hypothesis that increases in hypothalamic PTP1B contribute to leptin resistance in response to a high-fat diet. While chronic increases in circulating leptin are sufficient to increase PTP1B, HF diets also directly stimulate hypothalamic PTP1B via a leptin-independent mechanism.