Obesity-An Update on the Basic Pathophysiology and Review of Recent Therapeutic Advances

Abstract

Obesity represents a major public health problem with a prevalence increasing at an alarming rate worldwide. Continuous intensive efforts to elucidate the complex pathophysiology and improve clinical management have led to a better understanding of biomolecules like gut hormones, antagonists of orexigenic signals, stimulants of fat utilization, and/or inhibitors of fat absorption. In this article, we will review the pathophysiology and pharmacotherapy of obesity including intersection points to the new generation of antidiabetic drugs. We provide insight into the effectiveness of currently approved anti-obesity drugs and other therapeutic avenues that can be explored.

Keywords: anti-obesity drugs; diabetes mellitus; energy balance; obesity; obesity metabolism.

Figure 1

Energy balance signals integration. In the blue quadrant there is a simplified representation of hypothalamic energy balance regulation mechanisms: primary neurons in the arcuate nucleus include appetite-inhibiting neurons (red)–cocaine-and amphetamine-stimulated transcript peptide (CART) and proopiomelanocortin (POMC), which release peptides that stimulate the melanocortin receptors (MC3 and MC4). MC3/4R stimulation increases energy expenditure and decreases appetite. This circuit is stimulated by adiposity and anorexigenic signals. Peripheral signals related to long-term energy stores are produced by adipose tissue (leptin, adiponectin) and the pancreas (insulin). Gut hormones with incretin-, hunger-, and satiety-stimulating effects: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and potentially oxyntomodulin (OXM) improve the response of the endocrine pancreas to absorbed nutrients; GLP-1 and OXM also centrally reduce food intake; secretin (SCT) and cholecystokinin (CCK) released from the gut inhibit appetite by way of the vagus nerves, which stimulate hindbrain structures.

Figure 2

Obesity is linked to mitochondrial dysfunction and insulin resistance. In obesity, proinflammatory macrophages are attracted to the adipose tissue depot and release proinflammatory cytokines, which trigger, amongst other reactions, inflammation, increased oxidative stress, and mitochondrial dysfunction. Dietary nutrient excess leads to an overload of mitochondria with free fatty acids (FFA) and glucose, which impairs multiple mitochondrial functions (in red). The reduced beta oxidation leads to an increase in reactive oxygen species (ROS), which reinforces the mitochondrial damage and contributes to insulin resistance and adipose tissue dysfunction.

Figure 3

Summary of the mechanism of action for FDA/EMA approved anti-obesity drugs.