Adipocyte Maturation Arrest: A Determinant of Systemic Insulin Resistance to Glucose Disposal

An environment enriched with an excessive supply of food and lacking demand for physical activity requires adaptive response to “buffer” against metabolic imbalance. If utilization of excessive calories fails to fulfill this goal, deposition of triglyceride in adipose tissue is the natural barrier against the toxic effects of lipid and glucose in virtually all cell types (1, 2). Normal adipose tissue functions will guarantee protection against lipo- and glucotoxicity. This is accomplished through adipocyte differentiation from precursor cells and maturation to triglyceride-loaded adipocytes of various sizes. If unchanged, this condition will determine progressive increase in body fat content and weight gain. Different control mechanisms of adipocyte differentiation and maturation in various adipose tissue areas are likely responsible for variability in fat distribution between genders and among individuals.

For decades, research has focused on the role of body fat mass excess, and then fat distribution, on metabolic complications typically associated with obesity. We have witnessed a proliferation of literature in support of the detrimental effects of increased abdominal/truncal fat mass on glucose and lipid metabolism. Both visceral and sc abdominal/truncal fat deposition have been associated with systemic insulin resistance (3) and enhanced risk for associated health complications, such as type 2 diabetes and cardiovascular disease (3–6). Unfortunately, the clinical implications of this research have been rather limited. Although body mass index (BMI) and waist circumference are widely used as measures of fat mass and distribution and have a role in predicting risk for type 2 diabetes and cardiovascular disease, their clinical value is evident only when combined with other metabolic abnormalities, such as those defining the metabolic syndrome (7). Metabolically healthy obese persons are frequent in our clinics, and intervention for prevention of cardiovascular disease and type 2 diabetes in this group is questionable. More importantly, metabolically unhealthy nonobese persons are not easily identifiable as candidates for preventive treatment, based on fat mass and distribution. This is particularly evident in ethnic minorities of the U.S. population, such as the African-Americans, Hispanics, and Asians. Metabolic abnormalities, including insulin resistance, are more common in these groups at lower BMI and waist circumferences, compared with the European descent group (8, 9). Consequently, use of specific BMI and waist circumference targets have been suggested for different populations (10), but the overall result seems to be more confusion both for patients and physicians on the real value of these measurements. Given the growing need to optimize our health care resource allocation into prevention of chronic diseases, the lack of appropriate tools to identify patients at risk for the two major health complications of insulin resistance, type 2 diabetes and cardiovascular disease, is of significance. Recent trends toward research focusing on adipose tissue function and metabolic complications of obesity are promising. Adipose tissue function is now recognized to play a major role in metabolic homeostasis of both lipids and glucose. Identification of biomarkers of adipose tissue dysfunction may provide the much needed tools to identify a disease status (adiposopathy) that precedes and is the cause of metabolic complications, such as insulin resistance. Defining an adipose tissue dysfunction as a disease would be of value for regulatory agencies, pharmaceutical companies, and clinicians who could better focus therapy to the appropriate patient for prevention of adverse health consequences of glucose and lipid metabolism abnormalities, such as type 2 diabetes and cardiovascular disease.