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. Increasing numbers of investigators are refocusing obesity research along these lines. In this issue of the JCEM, Rogers et al. (11) identified epidermal growth factor receptor-1 (ErbB1) as a modulator of adipose tissue function. Using a combination of in vitro and clinical studies, their results suggest that ErbB1 is involved in promoting triglyceride storage in adipocytes, perhaps through maintenance of adequate peroxisome proliferator-activated receptor-γ activity. Decreased ErbB1 protein in sc abdominal adipose tissue was shown in insulin-resistant subjects and in those who developed type 2 diabetes. The possibility that ErbB1 is part of a network of regulators of adipocyte maturation is intriguing and opens an opportunity to better understand the role of defective adipocyte triglyceride synthesis in fat partitioning, lipid toxicity, and systemic insulin resistance to glucose disposal. Among other candidate mechanisms of adipocyte maturation, the ectonucleotide pyrophosphatase/phosphodiesterase-1 was recently shown to induce abnormalities in fat partitioning in association with systemic insulin resistance (12). In both instances, adipocyte maturation arrest can be viewed as a specific type of adipose tissue dysfunction or “adiposopathy” (13) linked to systemic insulin resistance. Other known types of adiposopathy, which have been associated with systemic insulin resistance, may or may not be exclusively related to adipocyte maturation arrest and include abnormal adipokine production, adipocyte leptin resistance, and adipose tissue inflammation. As schematically depicted in Fig. 1, adipocyte maturation arrest can mechanistically provide an explanation for the apparent dissociation between metabolic health and fat mass/distribution. In the presence of positive caloric balance, increased demand for triglyceride storage is normally met by compensatory triglyceride synthesis in maturing adipocytes. In scenario A, adipocytes are fully capable of accommodating fatty acids derived from lipolysis of triglycerides in circulating lipoproteins; no spillover of fatty acid will occur. Persisting adipocyte triglyceride synthesis unmatched by lipolysis will lead to progressive increase in body fat storage until a new level of caloric balance is accomplished. The patient could become overweight, obese, or even morbidly obese. In these circumstances, plasma fatty acids are not expected to be elevated, and substrate supply for ectopic fat deposition would be minimal. This scenario explains the coexistence of obesity and normal glucose/lipid metabolism. It is worthwhile mentioning that this is not an uncommon circumstance and that about 25% of obese adults are estimated to be insulin sensitive (14). Additionally, according to the National Health and Nutrition Examination Survey data, 32% of obese adults have one or less metabolic abnormalities carrying risk for cardiovascular complications (15). Fig. 1. Adipocyte maturation regulation can modulate overall caloric “buffering” function of adipose tissue. The other extreme is shown in scenario C of Fig. 1. In this case, adipocyte maturation arrest will reduce triglyceride storage capacity in adipose tissue. Consequent increase of fatty acid spillover into plasma will increase substrate availability for triglyceride synthesis in other tissues, such as liver, skeletal muscle, myocardium, or even pancreas (16, 17). The absence of acquired resistance to the lipogenic effects of insulin in the liver (18) makes this organ a major target of ectopic fat deposition. Consequent fatty liver actively contributes to systemic abnormalities of glucose metabolism, dyslipidemia, and various components of the metabolic syndrome (19–24). Elevated circulating fatty acid contributes to systemic insulin resistance also by promoting skeletal muscle switch from glucose to fatty acid utilization (25). Therefore, a common root for the metabolic cluster of abnormalities we observe in systemic insulin resistance could be identified in the inability to store new triglyceride (adipocyte maturation arrest) in conditions of persisting caloric excess. In this scenario, patients are expected to have insulin resistance shortly after positive caloric balance has begun, even in the absence of significant weight gain. This would explain the observation of metabolically unhealthy lean persons. Most of our patients likely belong to scenario B depicted in Fig. 1. According to this scenario, a defect in adipocyte maturation can occur at different stages of adipocyte growth. One can envision the possibility of genetic and metabolic regulator of the threshold at which triglyceride storage may come to a halt in a given adipocyte or group of adipocytes. The predicted result will be heterogeneity in adipocyte size distribution and degree of fat mass increase. Once this threshold is achieved, metabolic complications similar to scenario C will ensue. Importantly, metabolic complications will be observed at any level of either total or regional fat mass. Clearly, the studies of Rogers et al. (11) together with the growing literature on mechanisms of adipose tissue dysfunction and its link with the pathogenesis of systemic insulin resistance beg the need for a shift in the focus of clinical research from fat mass/distribution to adipose tissue function. Translational applications of the proposed mechanisms of adipocyte maturation arrest have the potential to help clinicians in better identifying patients at risk for type 2 diabetes and cardiovascular disease. Better understanding of these mechanisms in relation to systemic insulin resistance will certainly lead to new therapeutic opportunities for prevention of these major causes of morbidity and mortality in our population.