Despite high leptin levels, most obese humans and rodents lack responsiveness to its appetite-suppressing effects. We demonstrate that leptin modulates NPY/AgRP and alpha-MSH secretion from the ARH of lean mice. High-fat diet-induced obese (DIO) mice have normal ObRb levels and increased SOCS-3 levels, but leptin fails to modulate peptide secretion and any element of the leptin signaling cascade. Despite this leptin resistance, the melanocortin system downstream of the ARH in DIO mice is over-responsive to melanocortin agonists, probably due to upregulation of MC4R. Lastly, we show that by decreasing the fat content of the mouse's diet, leptin responsiveness of NPY/AgRP and POMC neurons recovered simultaneously, with mice regaining normal leptin sensitivity and glycemic control. These results highlight the physiological importance of leptin sensing in the melanocortin circuits and show that their loss of leptin sensing likely contributes to the pathology of leptin resistance.

Prepregnancy maternal obesity confers an increased risk of stillbirth, but the mechanisms are unknown. Maternal obesity is associated with placental inflammation. We considered that maternal diet may predispose to the increased risk of placental inflammation and stillbirth. We hypothesized that a chronic high-fat diet (HFD) is associated with abnormal uteroplacental circulation and placental inflammation. Here we used a nonhuman primate model to determine the effect of chronic HFD on the uterine and placental hemodynamics, placental histology, and inflammation in a prospective, observational study of 24 Japanese macaques. Overall, there was a statistically significant (38-56%) reduction in uterine volume blood flow from HFD animals, whether they were lean or obese. Consumption of a HFD, independent of obesity, increased placental inflammatory cytokines and the expression of Toll-like receptor 4. We show that HFD consumption by obese mothers with hyperinsulinemia also reduced volume blood flow on the fetal side of the placenta and significantly increased the frequency of both placental infarctions and stillbirth. These results suggest that a HFD, independent of obesity, decreases uterine volume blood flow. Maternal obesity and insulin resistance further exacerbates the placental dysfunction and results in an increased frequency of stillbirth.

ENRIORI, PABLO J., ANNE E. EVANS, PUSPHA SINNAYAH, AND MICHAEL A. COWLEY. Leptin resistance and obesity. Obesity. 2006;14(Suppl 5):254S-258S. The prevalence of obesity, and the human and economic costs of the disease, creates a need for better therapeutics and better understanding of the physiological processes that balance energy intake and energy expenditure. Leptin is the primary signal from energy stores and exerts negative feedback effects on energy intake. In common obesity, leptin loses the ability to inhibit energy intake and increase energy expenditure; this is termed leptin resistance. This review discusses the evidence in support of leptin resistance in mouse models and humans and the possible mechanisms of leptin resistance.