Treatment of Obesity in Mitigating Metabolic Risk

Abstract

Through diverse mechanisms, obesity contributes to worsened cardiometabolic health and increases rates of cardiovascular events. Effective treatment of obesity is necessary to reduce the associated burdens of diabetes mellitus, cardiovascular disease, and death. Despite increasing cardiovascular outcome data on obesity interventions, only a small fraction of the population with obesity are optimally treated. This is a primary impetus for this article in which we describe the typical weight loss, as well as the associated impact on both traditional and novel cardiovascular disease risk factors, provided by the 4 primary modalities for obtaining weight loss in obesity-dietary modification, increasing physical activity, pharmacotherapy, and surgery. We also attempt to highlight instances where changes in metabolic risk are relatively specific to particular interventions and appear at least somewhat independent of weight loss. Finally, we suggest important areas for further research to reduce and prevent adverse cardiovascular consequences due to obesity.

Keywords: cardiovascular disease; exercise; obesity; risk factor; weight loss.

Figure 1.. Typical changes in body weight and traditional cardiovascular disease risk factors via weight loss in obesity.

(A) This diagram represents average observed weight loss in clinical studies with lifestyle interventions (dietary modification and increased physical activity), pharmacotherapy and metabolic surgery. (B) This figure demonstrates the range of weight loss over which changes in traditional cardiovascular risk factors typically occur. Improvements in blood pressure, triglycerides and glycemia become noticeable with modest weight loss. Reductions in LDL-cholesterol and inflammatory markers require more substantial weight loss. Reductions in triglycerides, glycemia and inflammation particularly, continue to improve as weight loss increases and have the potential to be significantly impacted with substantial weight loss, whereas LDL-C and HDL-C generally improve only modestly. (Illustration Credit: Ben Smith)

Figure 2.. Weight loss-independent effects of exercise on cardiovascular disease risk in obesity.

Exercise improves multiple aspects of metabolic risk in obesity. Many of these happen at the level of the skeletal muscle and are mediated with skeletal muscle contraction which increases GLUT4 transporters at the cell surface, PGC1α expression, LPL activity, and induces IL-6 release. IL-6 increases circulating GLP-1 and has anti-inflammatory effects. Increased shear stress in the vasculature with exercise improves endothelial function and reduces blood pressure. Exercise is associated with reductions in visceral and epicardial adipose and adipose inflammation independent of weight loss. Loss of adipose tissue and reduced adipose inflammation contributes to a less atherogenic lipid profile characterized by increased HDL-C and larger HDL particles and reduced LDL-C and small LDL particles. Exercise-mediated changes in the activity of enzymes necessarily for HDL metabolism also play roles in increasing HDL size and HDL-C half-life in the circulation. (Illustration credit: Ben Smith)

Figure 3.

(A) Pathways mediating weight loss via either pharmacologic- or metabolic surgery-induced increases in GLP-1. Metabolic surgery and GLP-1 agonists increase signaling through central and peripheral GLP-1 receptors enhancing satiety and facilitating weight loss. Central receptor activation in the hyppothalamus increases satiety, decreases appetite and slows gastric emptying. Peripheral receptors slow gastric emptying and GI motility, enhancing satiety. (B) Weight loss-independent activity of GLP-1 in reduction of cardiovascular risk in obesity. As described in detail in the text, increased GLP-1 signaling improves traditional cardiovascular risk factors, reduces systemic inflammation, extensively benefits the vasculature and stimulates myocardial ischemic conditioning. (Illustration credit: Ben Smith)

Figure 4.. Weight loss-independent mechanisms of cardiovascular risk reduction in metabolic surgery.

Both RYGB and sleeve gastrectomy increase nutrient transit which results in increases in circulating PYY and GLP-1 which, in turn, improve glycemia, reduce inflammation and improve endothelial function. These activities contribute to cardiovascular risk mitigation following metabolic surgery. RYGB further increases levels of circulating bile acids which further stimulates GLP-1 release and may have additional positive effects on lipid profile (predominantly triglyceride lowering). Changes in the gut microbiome may also contribute to increased circulating bile acids after RYGB. (Illustration credit: Ben Smith)