The obesity pandemic: where have we been and where are we going?

Obesity, a new pandemic, is associated with an increased risk of death, morbidity, and accelerated aging. The multiple therapeutic modalities used to promote weight loss are outlined with caution, especially for patients who are very young or old. Except for very rare single gene defects, the inheritance of obesity is complex and still poorly understood, despite active investigations. Recent advances that have shed light on the pathophysiology of obesity are the recognition that 1) excess fat is deposited in liver, muscle, and pancreatic islets; 2) fat tissue secretes a large number of active signaling molecules including leptin, adiponectin, and resistin, as well as free fatty acids; and 3) activated macrophages colonize the adipose tissue. Other candidates for key roles in the causes and consequences of obesity include 1) metabolic programming, where food acts as a developmental regulator; 2) the constellation of defects known as the "metabolic syndrome;" 3) cortisol overproduction in the adipose tissue; and especially, 4) insulin resistance. The possible etiologies of insulin resistance include cytokine excess, elevated free fatty acids, and hyperinsulinemia itself, as with transgenic overproduction of insulin in mice.