A person's body weight is determined by the factors hunger/satiation and energy intake/energy use. Ever since hereditary forms of obesity were discovered in mice in the 1950s, researchers have investigated the regulation of these factors. About 20 years ago, it was found that the so-called ob mouse (for obese) is missing a satiety factor that would normally circulate in its blood. Finally, in 1994, the ob gene was cloned. The expression product, leptin, consists of 167 amino acids. Administering lep-tin to ob mice normalized their body weight by reducing energy intake and increasing energy use, mainly by increasing body temperature. Leptin and its effects have since been confirmed in humans.
Leptin controls energy uptake and use by regulating various satiety factors (A) in the hypothalamus, such as neuropep-tide Y (NPY) or glucagon-like peptide 1 (GLP-1). Since leptin is synthesized in white adipocytes, fat mass functions as a sort of central control sensor. The expression of the ob gene is greatly enhanced by glucocorticoids and insulin. Consequently, high insulin levels should result in low body weight, contrary to what actually happens. These contradictory findings can only be explained by assuming problems with various receptors. The CNS receptors for leptin, neuropeptide Y and other transmitters are now known. However, until recently, the connection between leptin and cellular energy consumption through thermogenesis had not been established.
It has been known since 1994 that there is a protein in brown fatty tissue called UCP1 (uncoupling protein 1) which, at the inner mitochondrial membrane, is able to assume the function of the respiratory chain proteins (B). When it does, the electrochemical gradient (H+ electron chain) is not used to produce energy in the form of ATP. Rather, free fatty acid anions (FFA ) serve as proton acceptors—a "nonsensical" cycle that produces only heat and thereby "wastes" energy. Finally, in 1997, UCP2 was discovered, which, unlike UCP1, is found in many tissues. Neither its significance nor its regulation is known in detail yet. Based on its more widespread occurrence, UCP2 may be responsible for regulating basal metabolic rate and have a role in the development of obesity. Recently, an additional isoform, UCP3, was discovered in skeletal muscle, and traces in all fatty tissues.
These discoveries have raised great expectations for a pharmacological therapy of obesity and of type 2 diabetes. It needs to be pointed out, though, that in humans and animals, regulation is usually polygenic. For instance, it has been shown in humans that a polymorphism of the p3-adrenergic receptor is more common in obese individuals. It is likely that more such genes, each of which contributes a small part to obesity, will be discovered.
- A. Homeostasis of Body Weight
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