Molecular Switch In The Brain Controls Weight Gain

Using mouse models of obesity, Japanese researchers have identified a molecule in the brain that promotes leptin resistance, which leads to weight gain.

AsianScientist (Sep. 20, 2017) – Scientists in Japan have identified a signaling pathway in the mid-brain region that controls food intake and obesity. They published their results in the journal Scientific Reports.

Leptin is an adipocyte-derived hormone that stimulates hypothalamic neurons to strongly inhibit food intake. Leptin signaling in the hypothalamus, a part of the mid-brain, thus plays a crucial role in the regulation of body weight. Leptin resistance, in which leptin signaling is disrupted, is a major obstacle to the improvement of obesity. However, the exact mechanisms underlying leptin resistance in obese patients have yet to be elucidated.

In this study, a research group led by Professor Masaharu Noda of the National Institute for Basic Biology in Japan demonstrated that protein tyrosine phosphatase receptor type J (PTPRJ) inhibits leptin signaling, and that the induction of PTPRJ in the hypothalamus is the cause of leptin resistance.

They showed that PTPRJ is expressed in hypothalamic neurons together with leptin receptors, and that PTPRJ inhibits the activation of the leptin receptor through dephosphorylation of JAK2, a protein tyrosine kinase associated with the leptin receptor. PTPRJ-deficient (PTPRJ-KO) mice showed no growth retardation. However, weight gain in PTPRJ-KO mice was lower compared with wild-type mice, due to reduced food intake and adiposity.

Importantly, PTPRJ expression in the hypothalamus of wild-type mice was upregulated by diet-induced obesity. In contrast, PTPRJ-KO mice did not exhibit leptin resistance since they were unable to produce PTPRJ. The overexpression of PTPRJ in the hypothalamus was sufficient to induce leptin resistance in lean mice.

These results strongly indicated that PTPRJ plays critical roles in the development of leptin resistance. The inhibition of PTPRJ may therefore be a potential strategy for countering the epidemic of obesity.

The article can be found at: Shintani et al. (2017) PTPRJ Inhibits Leptin Signaling, and Induction of PTPRJ in the Hypothalamus Is a Cause of the Development of Leptin Resistance.


Source: National Institutes of Natural Sciences; Photo: National Institute for Basic Biology.
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