Of dieting and leptin

Abstract

The past decade has witnessed a steady surge in the incidence of obesity and obesity-related disorders. Although not considered as a disease itself, obesity is a risk factor for several, potentially life-threatening diseases including type II diabetes mellitus and ischemic heart diseases. With its increasing incidence, the global costs for treating obesity-related disorders are also escalating. That said, decreasing one’s caloric intake in an attempt to lose weight is popular amongst overweight individuals, but failure to maintain reduced body weight following dietary regimens is more the rule than the exception. Interestingly, changes in body weight are associated with fluctuations in circulating leptin levels. Leptin is a peptide secreted from fat tissue that informs the brain over peripheral energy stores. The circulating amounts of leptin are directly proportional to the amount of fat tissue. The Neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) neurons, often referred to as the first order neurons, are under direct control of leptin. Interestingly, the effects of leptin on POMC and NPY neurons are antagonistic. Leptin decreases the firing of NPY neurons while increasing that of POMC neurons. Moreover, expression of the orexigenic peptide NPY is suppressed by leptin while that of anorexigenic peptide POMC is increased. Thus, in a starved or underfed state, when circulating leptin levels are low, higher NPY and lower melanocortin levels promote hunger and the drive to eat. In contrast, in a fed state leptin levels are increased and thus hunger is suppressed by decreasing NPY and increasing melanocortinergic peptide expression. Since leptin levels decrease during weight loss, in the current thesis we studied whether a fall in leptin levels triggers motivational and thermoregulatory adaptations during weight loss.

The first part of the thesis specifically looks into the role of Neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) peptides on different brain areas (ventral tegmental area, nucleus accumbens and lateral hypothalamus) on motivation for food rewards. The second part of the thesis focuses on the physiological effects of caloric restriction (i.e. drop in leptin levels) on previously obese rodents, thereby mimicking dieting conditions in humans. Delving specifically into the thermogenic adaptations during dieting and weight loss, it reports that small changes in thermogenesis could have measurable consequences for weight loss.