Adipose tissue pathophysiology: A conference report

The rising prevalence of obesity and the underlying increase in adipose tissue that this reflects prompted the American Association of Clinical Endocrinologists to convene a consensus panel of experts in Washington, D.C., on March 20 to examine the role of the quantity and distribution of adipose tissue to the increased risk for cardiometabolic disease.

The conference began with Samuel Klein, MD, William H. Danforth professor of medicine and nutritional science, Washington University School of Medicine, who discussed the role of hepatic fat and visceral fat in insulin resistance and cardiometabolic diseases. Non-alcoholic liver disease is one of the most important clinical diseases for the hepatologist. Hepatic fat is more strongly related to insulin resistance than visceral fat.

A study that matched individuals for visceral fat showed that insulin sensitivity was reduced in those with higher levels of liver fat; conversely, there was no difference in insulin sensitivity or glucose uptake if intrahepatic fat levels were the same but visceral adipose tissue different. Calorie restriction reduces hepatic lipid and restores insulin sensitivity, but removal of fat by liposuction, which only removes subcutaneous fat, has no effect on glucose or insulin sensitivity. Thus, where fat is located is an important consideration is obesity.

George A. Bray

There are two types of fat cells — white fat cells and brown fat cells — which originate from different precursor cells.

At the meeting, I outlined the developmental sequence for both types of adipocytes. There are more than a dozen intracellular molecules and a half dozen extracellular molecules that are involved in the maturation of white adipocytes.

Obesity can be characterized as hyperplastic or hypertrophic, depending on whether the fat cells in the body are increased in number (hyperplastic) or primarily in size (hypertrophic). As fat cells enlarge, they become hypoxic, and this is associated with the production of collagen, which increases the fiber around fat cells and contributes to the development of insulin resistance. Adiponectin, one of the principal products of the fat cell, enhances the ability of fat cells to differentiate and may overcome these limitations on fat cell growth. These effects of adiponectin are primarily in subcutaneous fat cells and emphasize the differential responses of fat cells in different regions of the body. Some readily expand with increased caloric intake; others are resistant.

Genetic factors

The role of genetic factors in the biology of adipocytes was described by Nicola Abate, MD, an associate professor of internal medicine at University of Texas Southwestern Medical Center.

From genome-wide association studies, 17 genes have been identified as contributors to the differences in BMI, but only account for a small amount of individual variation (2%). Of these, the FTO gene makes the largest contribution, primarily through differences in food intake. Those who are homozygous for the FTO gene are 2 kg to 3 kg heavier than those who are not.

Ethnic variations are also evident in the quantity of fat and its distribution in the visceral and subcutaneous compartment. One gene — ENPP1/PC1 — appears to be important in this difference and, interestingly, its effects on body weight were blunted in the lifestyle and metformin arms of the Diabetes Prevention Program.

Fat is an endocrine organ. The fat cell has many secretory products and Michael Jensen, MD, of the Endocrine Research Unit at Mayo Clinic, Rochester, Minn., focused on several. Leptin is a feedback signal from fat to the brain about stores of body fat. It plays a key role in the response to caloric deprivation. Treatment with leptin reverses many metabolic consequences of calorie restriction; however, leptin treatment of obese people failed to produce much weight loss.

Adiponectin is an endocrine signal from fat that serves as a marker for insulin sensitivity. Resistin is another endocrine product of the fat cell that seems to be more important in rodents than humans. Two cytokines, interleukin-6 and tumor necrosis factor-alpha, are released from fat, but IL-6 comes from many other tissues.

Adipose tissue is also an immune organ, as its production of cytokines indicates. The presentation by Hollander expanded on the role of cytokines from adipose tissue that had been introduced in the discussion of IL-6 and tumor necrosis factor-alpha.

Lewis Landsberg, MD, Irving C. Cutter professor of medicine and dean emeritus of the Feinberg School of Medicine, Northwestern University, identified three primary mechanisms that underlie the relationship between obesity and blood pressure. The first is hyperinsulinemia. Hyperinsulinemia and insulin resistance are associated with hypertension in clinical and population studies. Insulin increases sympathetic activity that may mediate this response to insulin.

Leptin, a second mechanism, rises with obesity and is known to increase activity of the sympathetic nervous system. Finally, angiotensinogen from the fat cell is the substrate for angiotensin II, which can increase the sympathetic nervous system and BP. The bright side of the picture is that BP can be improved by dietary strategies.

Obesity factor

Two key presentations at the AACE conference focused on the issue of adipose tissue in metabolic disease and obesity as a factor leading to the increase in adipose tissue. The premise by J. Michael Gonzalez-Campoy, MD, PhD, medical director and CEO, Minnesota Center for Obesity, Metabolism and Endocrinology, Eagan, Minn., was that obesity is a biological, preventable and treatable disease, and that by treating it, the complications of obesity are preventable.

He reviewed many systems that are adversely affected in obesity. He viewed obesity as a disease, much like the Obesity Society. He viewed impaired fasting glucose, type 2 diabetes and the risk for cardiovascular disease as a continuum. The fact that metabolic diseases occur in all categories of BMI suggests that assessing adiposity may provide an improved way to evaluate risk, according to Gonzalez-Campoy. Because insulin resistance predicts diabetes, independent of obesity, measurements of body fat and insulin responsiveness may provide alternatives to the BMI for evaluating the obese patient.

He said a new term — “adiposopathy” — might help with the identification of individuals at risk for metabolic disease. However, the issue of intrahepatic fat noted earlier by Klein poses a problem to this approach.

In another presentation, Harold Bays, MD, medical director and president, Louisville Metabolic and Atherosclerosis Research Center, Kentucky, expanded on the theme of adipose tissue and disease. As he said, not all overweight patients have metabolic disease and, conversely, not all patients with metabolic disease are overweight. The key issue is to diagnose those patients who have the metabolic diseases. Their adipose tissue may have impaired adipogenesis that is enhancing the insulin resistance underlying many of the metabolic abnormalities. In addition to limited adipogenesis, the adipose tissue of individuals with metabolic abnormalities may have increased numbers of inflammatory cells in their fat tissue that may exacerbate the problem. For the endocrinologist, the challenge is to reduce the quantity of dysfunctional adipose tissue.

The presentation by Jeffrey I. Mechanick, MD, director of metabolic support and clinical professor of medicine in the division of endocrinology, diabetes and bone disease at Mount Sinai Hospital, focused on nutrition, physical activity and adipose tissue function in relation to metabolic disease.

AACE has developed the Power of Prevention program, which emphasizes healthy eating, healthy foods and regular physical activity. Mechanick discussed dietary factors that modulate immune responses, such as antioxidants. He also noted the potential risks from the endocrine disruptors attributed to a number of additives.

The conference ended on a note of optimism that there may be ways of helping patients with metabolic disease use diet, physical activity and medications to reduce the negative contribution of adipose tissue. Louis J. Aronne, MD, clinical professor of medicine at Weill Cornell Medical College, said the health care professional can help patients avoid medications that cause weight gain. He also noted that the use of current medications can be beneficial when used appropriately.

George A. Bray, MD, is Boyd Professor in the Pennington Center at Louisiana State University.

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