Approaches to the Pharmacological Treatment of Obesity

Victoria Salem; Stephen R Bloom

Disclosures

Expert Rev Clin Pharmacol. 2010;3(1):73-88. 

In This Article

Understanding the Neuroendocrine Control of Energy Homeostasis

Understanding the complex physiology of energy balance is vital for the development of safer and more effective long-term weight-loss pharmacotherapy, as an alternative to risk-laden surgical procedures. We have observed many advances in this field of research over the past two decades, and the following section provides a brief overview. The crucial areas of the brain co-ordinating energy and bodyweight homeostasis are the brainstem and hypothalamus. Peripheral neural and endocrine signals bringing information regarding energy availability are integrated with signals from higher brain centres (for example, regarding reward, stress or mood) to regulate appetite and control energy expenditure. Insulin from the pancreas and circulating humoral factors from adipose tissue (adipokines such as leptin) interact with CNS circuits to relay information regarding long-term energy stores.[13,14] Gastrointestinal hormones, which also act in a neuroendocrine fashion, are released on a meal-to-meal basis and signal short-term nutrient availability (this is summarised in Figure 1). Upon meal ingestion, vagal afferents are triggered by stretch receptors, nutrient chemoceptors and receptors for locally released gut hormones. These neurones converge in the nucleus of the tractus solitarius (NTS) of the brainstem. Close to this is the area postrema (AP), a region relatively deficient in blood–brain barrier and a second site for circulating hormones to influence these neuronal circuits. A gut–brain reflex circuit is completed by vagal efferents projecting back from the NTS to the gastrointestinal tract, to modulate digestive functions. In addition, projections from the brainstem carry signals upwards to the hypothalamus, which is the seat of homeostatic energy balance.[15] The arcuate nucleus (ARC) of the hypothalamus contains two populations of neurones, which have opposing effects on food intake. Orexigenic neurones (i.e., those stimulating food intake) in the medial ARC express neuropeptide Y (NPY) and Agouti-related protein (AgRP). Laterally located anorexigenic neurones (i.e., those inhibiting food intake) express a-melanocyte-stimulating hormone (a–MSH) derived from pro-opiomelanocortin (POMC), and cocaine- and amphetamine-regulated transcript (CART).[16] The relative tone of these two sets of opposing neurones is delicately altered by numerous neuroendocrine inputs. Signals arrive from the brainstem conveying a huge amount of information from the gastrointestinal tract as already described. The median eminence, an area deficient in blood–brain barrier that is close to the ARC, provides access for circulating factors such as leptin and gut hormones to directly affect the activity of appetite-regulatory neurones. There is additional influence from the many interconnections with higher brain centres inputting information such as reward drives and mood. In turn, the ARC projects neurones to the paraventricular nucleus (PVN) of the hypothalamus where responsive effects on energy expenditure arise, including changes in basal metabolic rate (via the thyroid axis), sympathetic outflow and thermoregulation.[16]

Figure 1.

Circulating factors are able to directly influence neuronal transmission in the brainstem and hypothalamus as well as activating vagal afferents.
Leptin and insulin are signals of long term energy stores. Gastrointestinal peptide hormones tract which signal short term nutrient availability on a meal-to-meal basis. Stomach-derived ghrelin is the only gut hormone released during fasting and is a meal initiator. The remaining gut hormones are released post prandially: pancreatic polypeptide and amylin from the pancreas, and cholecystokinin, peptide YY and the incretins glucagon-like peptide-1 and oxyntomodulin from the intestine. CCK: Cholecystokinin; GLP: Glucagon-like peptide; OXM: Oxyntomodulin; PP: Pancreatic polypeptide; PYY: Peptide YY.

Monogenic forms of obesity, although very rare, have helped delineate some of the central pathways involved in appetite regulation. For example, humans with homozygous deficiency of POMC or the melanocortin-4 receptor (which is the receptor for a-MSH from anorexigenic neurones) develop severe, early onset obesity.[17] Interestingly, NPY knockout mouse models do not exhibit a lean phenotype as expected, but do display normal food intake[18] – most likely owing to the activation of numerous compensatory pathways protecting against starvation. These findings lend support to the generally held view that organisms possess an evolutionarily programmed tendency to protect against weight loss more than weight gain.

Understanding the genetic contribution of more common forms of obesity is an area of intense recent research, with the hope that this may help to identify novel pharmacological approaches. Observationally, it is clear that some people are protected more than others against the obesogenic effects of our modern lifestyles. In fact, twin studies suggest that 70% of variation in adiposity within the population is due to genetic factors.[19] Thus, the commonly held view that obesity is simply a consequence of the individual's decision to eat too much and exercise too little is an oversimplification. The salient question that remains largely unanswered is: what biologically determined factors make it difficult for some more than others to maintain a normal bodyweight? We are a long way from explaining the high heritability of the condition and, as is true of many common and complex diseases, a large number of genetic factors are likely to be interplaying. The advent of high-powered genome-wide association studies is helping to pave the way to identifying new candidate genes, with the FTO gene in obesity as a recent example.[20] The obesity high-risk FTO allele is common in Caucasians, and homozygous adults are 2–3 kg heavier, with higher BMI and reduced satiety observable from childhood. FTO codes for the enzyme 2-oxoglutarate-dependent nucleic acid demethylase,[21] which is particularly highly expressed in the hypothalamus, although the exact molecular mechanism underlying the FTO association with obesity remains to be elucidated.

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