Pharmacotherapy for Obesity

A Field in Crisis?

Wiebke Fenske; Jennifer Parker; Stephen R Bloom

Disclosures

Expert Rev Endocrinol Metab. 2011;6(4):563-577. 

In This Article

Modulation of Appetite & Energy Expenditure

The balance of energy intake and expenditure by the brain relies on the complex integration of signals originating in the periphery with those from diffuse neuronal networks within the brain itself. In response to these signals, the brain produces a coordinated response to any change in nutritional status to maintain energy homeostasis. This response can take the form of altered appetite and/or energy expenditure.

Putative satiety hormones and neurotransmitters involved in energy regulation circuits have been key targets for obesity drug development over the last decade (Figure 1). Despite this focus, there are no current anti-obesity treatments targeting these circuits. In fact, all three anti-obesity agents under FDA review in 2010 (a 5-HT2C receptor agonist lorcaserin, a phentermine–topiramate combination (Qnexa®; VI-0521, Vivus) and a naltrexone–bupropion combination (Contrave®, Orexigen Therapeutics Inc.) have been rejected and previously effective agents (phentermine, rimonabant and sibutramine) have been withdrawn due to safety concerns. In examining what went wrong with these drugs, it is important to consider whether their failings are indicative of all drugs of their specific classes or indeed likely to be drawbacks of all centrally acting agents. This could have implications for drugs targeting the CNS currently in early-stage clinical trials.

Figure 1.

The brain integrates multiple peripheral and neural signals to control the regulation of energy homeostasis, maintaining a balance between food intake and energy expenditure. Peripheral factors indicative of long-term energy status are produced by adipose tissue (leptin and adiponectin) and the pancreas (insulin), whereas the acute hunger signal ghrelin (produced in the stomach) and satiety signals such as the gut hormones PYY(3–36), PP, amylin and OXM indicate near-term energy status. The incretin hormones GLP-1, GIP and potentially OXM improve the response of the endocrine pancreas to absorbed nutrients. Further feedback is provided by nutrient receptors in the upper small bowel and neural signals indicating distention of the stomach's stretch receptors, which are primarily conveyed by the vagal afferent and sympathetic nerves to the nucleus of the solitary tract (NTS) in the brainstem. The arcuate nucleus (ARC) of the hypothalamus, which is located between the third ventricle and the median eminence, integrates these energy homeostatic feedback mechanisms. It accesses the short- and long-term hormonal and nutrient signals from the periphery via semi-permeable capillaries in the underlying median eminence and receives neuronal feedback from the NTS. These collated signals act on two distinct subsets of neurons that control food intake in the ARC, which act as an accelerator and a brake respectively. The first subset coexpresses the orexigenic (appetite-stimulating) agouti-related peptide and neuropeptide Y (NPY) neurotransmitters, acting as an accelerator in the brain to stimulate feeding. The other neuronal population releases the anorexigenic cocaine- and amphetamine-regulated transcript and pro-opiomelanocortin neurotransmitters, both of which inhibit feeding. Both neuronal populations innervate the paraventricular nucleus, which, in turn, sends signals to other areas of the brain. These include hypothalamic areas such as the ventromedial nucleus, dorsomedial nucleus and the lateral hypothalamic area, which modulate this control system. Neural brain circuits integrate information from the NTS and multiple hypothalamic nuclei to regulate overall body homeostasis.
CCK: Cholecystokinin; DVC: Dorsal vagal complex; GIP: Glucose-dependent insulinotropic peptide; GLP-1: Glucagon-like peptide-1; OXM: Oxyntomodulin; PP: Pancreatic polypeptide; PYY: Peptide YY.

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