Obesity

Over half of USA and UK citizens are overweight or obese. In a few instances obesity is genetic; animals and humans that lack either functional leptin or leptin receptors (and hence have leptin resistance) are obese, as are those with excessive ghrelin concentrations. However, the overwhelming majority of people are overweight because over the long term their energy expenditure is lower than their energy intake. Experiments in that obese individual must work to obtain food suggest they respond more to external cues (how appetizing food seems) than to internal cues (hunger and satiety) than lean people. Basal metabolic rate (BMR) is related to lean body mass and because obese people have much the same lean body mass as lean individuals their BMRs do not differ on average. However, they have poorer capacity for energy expenditure.

Most humans with obesity have elevated plasma leptin concentrations—reflecting the size of their fat stores—but fail to respond to it. This leptin resistance means that despite having leptin concentrations that reflect their weight, the set point of body fat they defend by energy homeostasis is raised. In mice leptin resistance is triggered by a high fat diet, which acts by suppressing leptin receptor signal transduction in the arcuate nucleus.

Potential pharmacological treatments for acquired obesity include NPY, orexin, or endocannabinoid receptor antagonists and melanocortin, CART, or CRH receptor agonists. Many of these interventions are such as to be problematic; for example, orexins are included in wakefulness as well as feeding and CRH receptor agonists are anxiogenic.