In contrast, we identify clear negative consequences of chronic central AMPK activation—principally, ghrelin-dependent hyperphagia and potentially centrally mediated upregulation of hepatic de novo lipogenesis—ultimately overwhelming the beneficial peripheral effects and resulting in obesity and frank systemic insulin resistance, the adverse glucoregulatory consequences of which are further exacerbated by abnormal GSIS. This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.