Obesity therapy: altering the energy intake-and-expenditure balance sheet

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Abstract
Obesity is a chronic disorder of energy imbalance, whereby a long-term excess of energy intake over expenditure leads to the storage of that excess energy as fat. Pharmacological approaches to the management of obesity include altering the balance between energy intake and expenditure and/or altering the partitioning of nutrients between fat and lean tissue. A reduction in absorbed energy can be achieved by altering the amount and type of food ingested or by interference with its absorption. This could be achieved by amplifying the effects of natural anorexigenic signals. These include the adipocyte-derived hormone leptin, as well as the hypothalamic melanocortins that act downstream of leptin. A wide range of other neuropeptides are now considered to be involved in the control of appetite, and all are potential therapeutic targets. Reducing food intake can also be achieved by interfering with natural orexigenic signals. These include neuropeptide Y, melanin-concentrating hormone, and the recently described stomach-derived hormone ghrelin. Pharmacotherapy targeted at molecular pathways that regulate adaptive thermogenesis provides a plausible means of producing a sustained and safe method of increasing total energy expenditure. Increased expression of novel transcription factors, co-activators and translational regulators, such as PGC1 (peroxisome proliferator-activated receptor-γ co-activator 1), FOXC2 (forkhead box C2) and EIF4EBP1 (eukaryotic-translation-initiation-factor-4E binding protein 1), might promote the development of mitochondrial-rich brown adipocytes in white-adipose-tissue depots. Tissue-specific overexpression of UCP3 (uncoupling protein 3) in skeletal muscle represents a potentially interesting means of preventing diet-induced obesity. Beneficial metabolic effects might be expected from agents that inhibit the accumulation of fat mass relative to lean mass. Inhibitors of peroxisome proliferator-activated receptor-γ (PPARγ) or retinoid X receptor-α (RXRα) function could prevent the differentiation of pre-adipocytes to mature fat cells, therefore limiting adipose-tissue mass.