Читать книгу Clinical Obesity in Adults and Children - Группа авторов - Страница 79

The initial observations in this field were made as a result of positional cloning strategies in two strains of severely obese mice (ob/ob and db/db). Severely obese ob/ob mice were found to harbor mutations in the ob gene resulting in a complete lack of its protein product, leptin [24]. Administration of recombinant leptin reduced the food intake and body weight of leptin‐deficient ob/ob mice and corrected their neuroendocrine and metabolic abnormalities. The signaling form of the leptin receptor is deleted in db/db mice, which are consequently unresponsive to endogenous or exogenous leptin. The physiologic role of leptin in humans and rodents might be to act as a signal for starvation because as fat mass increases, further rises in leptin have a limited ability to suppress food intake and prevent obesity [25].

Considerable attention has focused on deciphering the hypothalamic pathways that coordinate the behavioral and metabolic effects downstream of leptin. The first‐order neuronal targets of leptin action in the brain are anorectic (reducing food intake) pro‐opiomelanocortin (POMC) and orexigenic (increasing food intake) neuropeptide‐Y/agouti‐related protein (NPY/AgRP) neurons in the hypothalamic arcuate nucleus, where the signaling isoform of the leptin receptor is highly expressed [26]. In the fed state, leptin stimulates POMC expression; POMC is sequentially cleaved by prohormone convertases to yield peptides, including α‐melanocyte‐stimulating hormone (MSH) which suppresses food intake by signaling through the melanocortin 4 receptor (MC4R). In fact, targeted disruption of MC4R in rodents leads to increased food intake, obesity, severe early hyperinsulinemia, and increased linear growth; heterozygotes have an intermediate phenotype compared to homozygotes and wild‐type mice [27].