1989 McCollum Award lecture. Genetic and hypothalamic mechanisms for obesity--finding the needle in the haystack

The elements of a feedback system for regulating body fat stores consists of an afferent limb providing feedback signals to the central controller in the brain, which integrates information from the sensory and autonomic nervous systems with signals from the internal milieu and modulates ingestive behavior and thermogenic components of the adrenergic nervous system. The search for defective mechanisms that produce obesity has utilized animals with genetic, hypothalamic, and dietary types of obesity. In all three cases, obesity is associated with an absolute or relative decrease in the activity of the sympathetic nervous system. Experimental situations associated with reduced activity of the sympathetic nervous system are generally accompanied by increased food intake and vice versa. Hypothalamic obesity results from damage to the ventromedial hypothalamus, which disrupts modulation of the autonomic nervous system by nutrient and hormonal signals. Recessively inherited obesity may result from failure to modulate the steroid-receptor complex interaction with the promoter region of the genome. Impaired acetylation of melanocyte-stimulating hormone (MSH) may be involved in the development of obesity in the obese yellow mouse. In all cases adrenalectomy arrests the progression or reverses the obesity. These findings further strengthen the autonomic and endocrine hypothesis for obesity.