Obesity: Pathophysiology and Management

Abstract

Obesity continues to be among the top health concerns across the globe. Despite our failure to contain the high prevalence of obesity, we now have a better understanding of its pathophysiology, and how excess adiposity leads to type 2 diabetes, hypertension, and cardiovascular disease. Lifestyle modification is recommended as the cornerstone of obesity management, but many patients do not achieve long-lasting benefits due to difficulty with adherence as well as physiological and neurohormonal adaptation of the body in response to weight loss. Fortunately, 5 drug therapies-orlistat, lorcaserin, liraglutide, phentermine/topiramate, and naltrexone/bupropion-are available for long-term weight management. Additionally, several medical devices are available for short-term and long-term use. Bariatric surgery yields substantial and sustained weight loss with resolution of type 2 diabetes, although due to the high cost and a small risk of serious complications, it is generally recommended for patients with severe obesity. Benefit-to-risk balance should guide treatment decisions.

Keywords: adipose tissue; antiobesity drugs; bariatric surgery; obesity; overweight; weight loss.

CENTRAL ILLUSTRATION:. Adiposity-Associated Major Risk Factors for Developing HF and Other Weight-Related Comorbidities

Increased plasma levels of free-fatty acids and cytokines, intracellular non-adipose tissue lipids (e.g., liposomes), and ectopic adipose tissue depots (e.g., within the visceral compartment) can contribute to systemic inflammation, insulin resistance, and over-activity of the sympathetic nervous system. The metabolic and anatomic effects of excess adiposity can lead to the development of type 2 diabetes, non-alcoholic fatty liver disease, obesity-related dyslipidemias, high blood pressure, and osteoarthritis. The cascade of these pathophysiologic mechanisms and associated diseases are the main contributors to obesity-related heart failure. RAAS, renin-angiotensin aldosterone system; SNS, sympathetic nervous system.

Figure 1.. Neural Pathways and Systems Controlling Ingestive Behavior and Energy Balance

Schematic diagram shows the three heavily interconnected major brain areas constituting the core processor for the control of ingestive behavior and its relation to the gastrointestinal tract and other peripheral organs involved in energy storage and utilization. The hindbrain is mainly concerned with meal size control, as it possesses all the elements to detect sensory information mediated by vagal afferents and circulating factors, and generate motor output associated with the ingestion, digestion, and absorption of food. The cortico-limbic system, consisting of large cortical areas, basal ganglia, hippocampus, and amygdala, is intimately connected to the hypothalamus and brainstem and provides the emotional, cognitive, and executive support for ingestive behavior. The hypothalamus via its connections with the other areas is central for the drive to eat and can potently modulate peripheral organs by autonomic and endocrine outflow. Reproduced with permission from Berthoud HR et al 2017 (17).

Figure 2.. Interrelations Among Adiposity Biomarkers

Upper Panels. Percent (%) body fat measured by dual-energy x-ray absorptiometry (DXA) versus BMI in participants of the National Health and Nutrition Survey (1999–2006). The data were fit with polynomial regression lines (R² men, 0.61; women, 0.68; both p<0.001). Note the curvilinear relation between BMI and % fat and the wide range of % body fat at any given level of BMI. Lower Panels. Waist circumference versus BMI in the same group of subjects as in the upper panels (R² men, 0.84; women, 0.80; both p<0.001). Horizontal lines are shown at waist circumference cut points (>102 cm men, >88 cm women) above which health risks increase within the BMI range 24.9–34.9. No additional waist circumference predictive value is present with BMI levels ≥35. Vertical lines identify BMI ranges for underweight (UW), normal weight (NW), overweight (OW), and obesity (OB) classes I to V. Definitions of severe obesity are variable in the medical literature.