Many of the peptide hormones described exert significant effects on energy metabolism via modulation of nutrient utilization or partitioning of fuel stores, and through effects on the hypothalamic feeding and energy circuits. Peripheral regulation of energy metabolism also occurs; the most significant example is the effect of sympathetic activation on p-adrenergic receptors. A number of well-characterized adrenergic receptor subtypes exist, and the signal transduction pathways activated following receptor activation have been well studied.
Sympathetic activation leads to two functional responses in fat cells mediated through the p3-adrenergic receptor.161 Increased lipolysis (breakdown of triglyceride stores to release fatty acids) occurs following receptor activation, adenylyl cyclase stimulation, and cAMP-dependent phosphorylation of hormone-sensitive lipase. In brown fat in particular, sympathetic nervous activation in response to cold or over-nutrition leads to increased oxygen consumption, food intake, and heat production via non-shivering thermogenesis.162 This effect is also mediated via the p3-adrenergic receptor, through production of transcription factors that coordinate synthesis of mitochondrial uncoupling proteins, electron transport components, and eventually, mitochondrial biogenesis.163
To demonstrate the requirement for p-adrenergic receptors in diet-induced thermogenesis, mice lacking the p3-adrenergic receptor were generated and shown to have modestly increased fat stores.164 Mice lacking p-adrenergic receptors 1, 2, and 3 were also produced.165 They were mildly obese, showed lowered metabolic rates, and were cold intolerant. On a high-fat diet, they became massively obese compared with wild-type controls.
Pharmaceutical companies have long been interested in the potential therapeutic use of p3-adrenergic agonists for the treatment of obesity and insulin sensitivity. Although such agents have produced beneficial effects in animal studies, the differences in receptor selectivity, tissue distribution, and subtype content in humans compared with rodents has been a stumbling block to rapid development in this area.166
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