Leptin Signaling in Obesity

Obesity is a multi-factorial trait primarily caused by an imbalance between energy intake and expenditure, leading to fat deposition in the body. This condition is exacerbated by an underlying genetic susceptibility to weight gain. Leptin is one of the 'satiety factors' that signals the status of energy stores to the hypothalamus. It is a peptide hormone produced mainly by adipocytes. Its production is regulated by indicators of positive energy status such as insulin and glucocorticoids. Adequate levels of leptin not only turn off the pathways for hyperphagia and obesity but also permit energy expenditure towards biological processes such as reproduction and growth.Leptin signals via the long form of its receptor LEPRb, which is found on POMC (pro-opiomelanocortin)/CART (cocaine and amphetamine-regulated transcript) and NPY (neuropeptide Y)/AGRP (agouti-related peptide) neurons in the hypothalamus. The former neurons produce the anorexigenic peptides POMC and CART, while the latter produce the orexigenic peptides NPY and AGRP. Under conditions of positive energy status, Leptin released by adipocytes binds to LEPRb on neurons in the hypothalamus, triggering multiple signal transduction pathways. For example, on being activated by ligand binding, LEPRb activates the JAK2-STAT3 pathway which eventually leads to increased expression of SOCS3 and POMC in POMC neurons while increasing SOCS3 and decreasing NPY expression in NPY neurons. SOCS3 inhibits leptin signaling by inhibiting JAK2 phosphorylation. Leptin also signals via the PI3K/AKT pathway leading to phosphorylation and nuclear exclusion of FOXO1, thereby indirectly inhibiting expression of NPY and AGRP while facilitating the expression of POMC. Leptin also inhibits ghrelin-induced activation of NPY neurons via the PI3K/PDE3 pathway. Thus, leptin in response to satiety mediates the induction of the anorexigenic peptide POMC while suppressing orexigenic peptides, NPY and AGRP. POMC is processed to α-MSH which then activates downstream energy expenditure pathways. Inhibition of NPY and AGRP leads to inhibition of hyperphagia and obesity.