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.
Obesity is associated with numerous health complications, which range from non-fatal debilitating conditions such as osteoarthritis, to life-threatening chronic diseases such as coronary heart disease, diabetes and certain cancers. The psychological consequences of obesity can range from lowered self-esteem to clinical depression. Despite the high prevalence of obesity and the many advances in our understanding of how it develops, current therapies have persistently failed to achieve long-term success. This review focuses on how fat mass can be reduced by altering the balance between energy intake and expenditure.
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- WHITE ADIPOSE TISSUE
(WAT). Fat tissue that contains predominantly 'white' adipocytes — cells that specialize in the storage of calorific energy as triglycerides, and its release as free fatty acids in response to changing energy demands.
Perturbations in plasma lipid and lipoprotein levels — for example, raised total and/or low-density lipoprotein cholesterol, reduced circulating levels of high-density lipoprotein cholesterol and elevated triglyceride levels — which might be associated with an increased risk of cardiovascular disease.
An increased desire to eat.
- ARCUATE NUCLEUS
The arc-shaped nucleus at the base of the hypothalamus.
- SEROTONERGIC AGONIST
A compound that mimics the actions of serotonin.
Causing an increase in food intake.
Causing a reduction in food intake.
Of the synapses or nerve fibres that liberate acetylcholine.
- BROWN ADIPOSE TISSUE
(BAT). Fat tissue that contains predominantly 'brown' adipocytes — cells that have abundant mitochondria (which gives the tissue a brown hue on macroscopic examination) and are specialized in the dissipation of energy through the generation of heat.
A catecholamine-secreting tumour that arises from chromaffin cells, usually of the adrenal medulla.
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Crowley, V., Yeo, G. & O'Rahilly, S. Obesity therapy: altering the energy intake-and-expenditure balance sheet. Nat Rev Drug Discov 1, 276–286 (2002). https://doi.org/10.1038/nrd770
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Obesity-promoting and anti-thermogenic effects of neutrophil gelatinase-associated lipocalin in mice
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Mammalian Rap1 controls telomere function and gene expression through binding to telomeric and extratelomeric sites
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Catecholamine Reuptake Inhibition Causes Weight Loss by Increasing Locomotor Activity and Thermogenesis