Currently more than the one-third of the world’s population is either obese or overweight. Obesity has rapidly become one of the largest global epidemics as it puts the individual at high risk for many life-threatening health conditions such as heart disease, cancer, and diabetes. According to the World Health Organization, over 17.3 million people, 8.2 million, and 3.4 million people worldwide die annually from heart disease, cancer, and diabetes, respectively. While individuals generally attribute obesity to a person’s poor eating habits and sedentary lifestyles, scientists believe that there is an underlying biological component that influences  many cases of obesity. Further understanding of  the biological causes behind obesity could  greatly impact the overall health of the world population as it would  potentially lower the prevalence of premature deaths.

     A person’s body weight correlates directly with two main factors: food consumption and energy expenditure. Any disruptions to the body’s regulation of energy homeostasis could result in obesity. The hypothalamus is the main region of the brain that is responsible for regulating the body’s energy homeostasis by sensing nutritional levels in the blood and subsequently controlling the food intake and energy expenditure. Neurons in the hypothalamus are directly activated or inactivated by leptin, the “master” hormone released by adipose tissues (fat) that essentially regulates  body weight. Leptin inactivates orexigenic neuropeptide Y/agouti-related neuropeptide, neurons that are responsible for stimulating appetite. Leptin simultaneously activates anorexigenic proopiomelanocortin neurons, which suppress appetite; these two groups of neurons aggregate in a region of the hypothalamus known as the hypothalamic arcuate nucleus (ARC). An increase in leptin levels after sufficient food intake causes the two groups of ARC neurons to jointly signal to the brain to strongly inhibit food intake and bring leptin levels back to equilibrium.

     However, past studies have shown that many obese individuals have an increased food intake despite high circulating leptin levels, a phenomenon referred to as leptin resistance. Two mechanisms have been proposed to explain leptin resistance: 1) decrease in leptin transport from the bloodstream to the hypothalamus region of the brain and 2) suppression of leptin signaling by an increase in negative regulatory molecules. A study conducted by Professor Masaharu Noda and colleagues from National Institute for Basic Biology attempts to uncover the exact mechanism underlying leptin resistance in obese patients.

     Their study demonstrates that protein tyrosine phosphatase receptor type J (PTPRJ) inhibits leptin signaling, and that presence of PTPRJ in the hypothalamus is a cause of leptin resistance. Leptin has been known to take part in the LepRb-JAK2 pathway. It binds to long-form leptin receptors (LepRb), which are strongly expressed in the ARC neurons. This then causes the receptor molecules to bind covalently together, or dimerize, and function as a single membrane bound protein. Dimerization of the two receptor molecules activates the associated non-receptor-type tyrosine kinase, Janus Kinase 2 (JAK2) through phosphorylation, which is the addition of a phosphate group. JAK2 then phosphorylates other proteins that leads to the activation of downstream signaling proteins. Based on previous research, PTPRJ is known to be a member a family of proteins known as the receptor like protein tyrosine phosphatases that is present in insulin target tissues such as adipose and brain tissue. Researchers suspected that PTPRJ negatively regulated the activation of receptor protein tyrosine kinases, such as JAK2. Experiments using Ptprj knock out mice demonstrated that PTPRJ inhibits JAK2 activation. Therefore, PTPRJ negatively regulates leptin signaling by dephosphorylating two separate residues on JAK2. As a result, the ptprj-KO mice exhibited lean phenotypes with lower amounts of adipose tissue due to reduced food intake through enhanced leptin signaling. Furthermore, diet-induced leptin resistance did not occur. These results not only indicate that there is a biological component to the prevalence of obesity, but they, also, articulate the neurobiological pathway of leptin that was previously undiscovered.  In the future, drug treatment inhibiting PTPRJ might serve as a novel strategy for improving the global health epidemic of obesity.


  1. Shintani T, Higashi S, Suzuki R, Takeuchi Y, Ikaga R,Yamazaki T, Kobayashi K, Noda M. (2017) PTPRJ Inhibits Leptin Signalin, and Induction of PTPRJ in the Hypothalamus Is a Cause of the Development of Leptin Resistance. Scientific Reports., 7, doi: 10.1038/s41598-017-12070-7

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