2-monopalmitin, but not 1-monopalmitin, enhances hypothalamic leptin responsiveness, energy balance, and glucose homeostasis under overnutrition

Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone for energy balance. Here, we found that 2-monopalmitin, but not 1-monopalmitin or palmitic acid, enhances hypothalamic leptin responsiveness in ex vivo brain slices. Centrally administered 2-monopalmitin markedly restored the leptin-induced suppression of food intake and reduction of body weight in diet-induced obese mice. Peripherally administered 2-monopalmitin also enhanced the anorectic effect of centrally administered leptin. Furthermore, daily 2-monopalmitin treatment protected against diet-induced body weight gain, and the energy expenditure of 2-monopalmitin-treated mice was significantly enhanced in a leptin-dependent manner. We also demonstrated that 2-monopalmitin lowered blood glucose levels, improved glucose and insulin tolerance, and protected mice against HFD-induced peripheral insulin resistance at the cellular and whole-body levels. Finally, treatment with 2-monopalmitin protected against LPS-induced leptin resistance, and decreased the hypothalamic levels of SOCS3, an inhibitor of leptin actions, and inflammatory cytokines. Altogether, our results showed that 2-monopalmitin in the brain, but not 1-monopalmitin or palmitic acid, is critical for linking overnutrition to the control of neural leptin actions.