Obesity Research

Causes of Obesity

The most common cause of obesity is a combination of low energy expenditure and high caloric intake. Environmental factors play a role in some cases and numerous susceptibility genes have been identified, including agouti-related peptide (AgRP) 199G - A polymorphism, FTO, NPC1, leptin, leptin receptors (Ob-R), and prohormone convertase-1. Certain psychiatric illnesses are associated with obesity, as are some genetic syndromes including Prader-Wili syndrome and MOMO syndrome. In addition, obesity can be secondary to other conditions such as hypothyroidism, Cushing's syndrome and growth hormone deficiency.

Many endogenous peptides effect appetite and hence have an influence on energy intake. Peripheral hormones effecting appetite include ghrelin, adiponectin, leptin, insulin, peptide YY (3-36), pancreatic polypeptide, glucagon-like peptide 1 (GLP-1), oxyntomodulin, amylin, cholecystokinin and bombesin. Other peptides act centrally to control appetite and these include neuropeptide Y, AgRP, melanocortin, orexin, galanin, α-melanocyte-stimulating hormone (α-MSH), cocaine and amphetamine-related transcript (CART) and neurotensin (NT).

Therapeutics

Treatment for obesity is focused on decreasing caloric intake and increasing energy expenditure. However, pharmacological interventions are available and include: orlistat, which inhibits pancreatic lipase to prevent uptake of fat from the diet; sibutramine, a serotonin-noradrenalin reuptake inhibitor (SNRI) that acts as an appetite suppressant; and rimonabant, a cannabinoid CB₁ receptor inverse agonist. These drugs only have a modest effect on weight. Other drugs, such as bupropion, are used 'off label' for their appetite-suppressing effects.

Due to the prevalence and economic burden produced by obesity, novel pharmacological treatments are needed. Many are focusing on inhibiting the effects of orexigenic peptides and agonizing the effects of anorexigenic peptides to reduce appetite and subsequently reduce food intake. Current interest is focused on ghrelin receptor antagonists, peptide YY (3-36), GLP-1 analogs, amylin analogs and orexin 1 receptor (OX₁) antagonists.