This issue of the JCI
features reviews on crucial aspects of obesity and related disorders. Sadaf Farooqi and Shwetha Ramachandrappa (31
) discuss monogenic syndromes, rare chromosomal abnormalities, and complex population genetics that have provided evidence for molecular interactions between the brain and other organs as well as a biological basis for eating behaviors associated with obesity. The discovery of leptin was a major milestone in our understanding of the molecular regulation of energy homeostasis (32
). Leptin is secreted by adipocytes and acts on the hypothalamus to inhibit food intake, increase energy expenditure, and reduce body fat. Leptin also regulates reproduction, immunity, intermediary metabolism, and bone biology, indicating a crucial role in integration of nutrition, normal cellular physiology, and pathological states. Laurent Gautron and Joel Elmquist (33
) review seminal studies preceding the identification of leptin and discuss advances in our understanding of the diverse actions of leptin since its discovery.
Sun and colleagues (34
) discuss the adaptation of adipose tissue in obesity. Adipose tissue is composed of triglyceride-filled cells (adipocytes), adipocyte precursors and other stromal cells, resident and infiltrating immune cells, and an extensive collagen network and blood supply. Proteins secreted by adipocytes (adipokines) act locally to regulate adipose tissue expansion and signal to various organs to control feeding, energy balance, and neuroendocrine and other functions. Dysregulation of adipose biology in obesity is associated with ectopic fat deposition (steatosis), insulin resistance, diabetes, cardiovascular complications, and other diseases.
Lipid droplets store neutral lipids in various cells. The surface of each lipid droplet is coated with proteins of the perilipin family, which regulate lipid metabolism under normal conditions and mediate excess accumulation of intracellular lipids associated with obesity, diabetes, and atherosclerosis. Greenberg et al. (35
) discuss the distribution patterns, regulation, and functions of these lipid droplet proteins and their putative roles in obesity, steatosis, inflammation, insulin sensitivity, and organ dysfunction.
Obesity results in significant alterations in components of the immune system in multiple organs. As described by Carey Lumeng and Alan Saltiel (36
), this leads to inflammatory changes in adipose tissue, liver, pancreatic islets, blood vessels, and hypothalamus. Changes in the levels of cytokines, chemokines, and activation states of different types of leukocytes have profound effects on organ structure and function; thus immunomodulatory strategies may be beneficial in the treatment of type 2 diabetes and other complications of obesity.
Pancreatic β cells secrete insulin, a key hormone that regulates blood glucose levels. Obesity is associated with insulin resistance, β cell expansion, and hyperinsulinemia (Figure ). In some patients, β cell dysfunction and/or a loss of β cell mass attenuates insulin production, leading to the development of diabetes mellitus. Genetics, nutrient toxicity, incretins, and growth factors have all been implicated in β cell failure and diabetes. In this series, Seino et al. (37
) explain the molecular mechanisms that control insulin secretion in normal versus obese individuals based on recent discoveries.
Natural history of type 2 diabetes (T2D).
The discovery that the gastrointestinal tracts of obese humans and mice harbor different microbes from their lean counterparts sparked enormous speculation that manipulating gut microbes might provide a means for weight reduction (38
). Here, Tilg and Kaser (39
) discuss the regulation of gut microbes by genetic and environmental factors and how this affects the immune system of the host and may lead to the development of metabolic complications of obesity.
Finally, Huang et al. (40
) review how circadian clocks align cellular biochemical processes and behavior. Disruption of circadian rhythms has profound effects on metabolism. Advances in understanding the molecular mechanisms linking circadian rhythms and metabolism disruption will provide novel insights and could suggest potential therapies for obesity, diabetes, cardiovascular disease, and other ailments associated with shift work, sleep deprivation, and other conditions that disrupt normal sleep-wake cycles.