Age-dependent changes in insulin action and body fat distribution are risk factors for the development of type 2 diabetes. To examine whether the accumulation of visceral fat (VF) could play a direct role in the pathophysiology of insulin resistance and type 2 diabetes, we monitored insulin action, glucose tolerance, and the expression of adipo-derived peptides after surgical removal of VF in aging (20-month-old) F344/Brown Norway (FBN) and in Zucker Diabetic Fatty (ZDF) rats. As expected, peripheral and hepatic insulin action were markedly impaired in aging FBN rats, and extraction of VF (accounting for ϳ18% of their total body fat) was sufficient to restore peripheral and hepatic insulin action to the levels of young rats. When examined at the mechanistic level, removal of VF in ZDF rats prevented the progressive decrease in insulin action and delayed the onset of diabetes, but VF extraction did not alter plasma free fatty acid levels. However, the expression of tumor necrosis factor-␣ and leptin in subcutaneous (SC) adipose tissue were markedly decreased after VF removal (by approximately three-and twofold, respectively). Finally, extracted VF retained ϳ15-fold higher resistin mRNA compared with SC fat. Our data suggest that insulin resistance and the development of diabetes can be significantly reduced in aging rats by preventing the age-dependent accumulation of VF. This study documents a cause-and-effect relationship between VF and major components of the metabolic syndrome. Diabetes 51: [2951][2952][2953][2954][2955][2956][2957][2958] 2002 A progressive increase in visceral adiposity is a common feature of aging, and epidemiological evidence supports its role as a prominent risk factor for insulin resistance, diabetes, and mortality from atherosclerotic cardiovascular disease (1-5). Among various body fat depots, the amount of visceral fat (VF) best correlates with insulin sensitivity in animal models and in humans. Insulin action is markedly impaired in individuals with visceral obesity (6,7), and epidemiological studies have shown that VF can account for most of the variability in insulin sensitivity in heterogeneous populations (2,4,6,7). However, these studies are associational in nature, and VF may be simply a "marker" of more complex endocrine and metabolic changes rather than playing a "causative" role in the pathogenesis of insulin resistance and its metabolic consequences. Putative mechanisms responsible for the modulation of insulin action by VF include increased portal release of free fatty acids (FFAs) (8,9) and/or abnormal expression and secretion of fat-derived peptides, such as resistin (10), leptin, ACRP30, and tumor necrosis factor-␣ (TNF-␣) (11).A consistent observation in the biology of aging is that chronic restriction of caloric intake in rodents markedly improves survival and prevents the onset of insulin resistance. We and others have hypothesized that the beneficial effects of caloric restriction (CR) on the metabolic alterations of aging are largely accounted for by its prevent...
The TSH population shifts to higher concentrations with age appear to be a continuum that extends even to people with exceptional longevity. The inverse correlation between TSH and FT4 in our populations suggests that changes in negative feedback may contribute to exceptional longevity.
These data demonstrate that cognitive dysfunction in centenarians is associated with a progressive decline in plasma HDL concentrations. This underscores the protective effects of increased plasma HDL and its role in maintaining superior cognition in longevity.
Increased fat mass, abdominal adiposity, and insulin resistance are typical findings in aging mammals and are frequently associated with leptin resistance and increased plasma leptin levels. To examine whether leptin's failure in aging is due to aging per se or to changes in body fat mass or distribution, we studied aging rats that underwent calorie restriction throughout their lives, maintaining their youthful body fat pattern and metabolic profile. Leptin's action was assessed by measuring its ability to regulate food intake, fat mass and its distribution, peripheral and hepatic insulin action, and its own gene expression in fat. Our results show that leptin's action is markedly diminished in aging rats, independently of their body fat pattern. Leptin's failure in this model suggests its causative role in the metabolic decline seen with aging. Diabetes 51: 1016 -1021, 2002 A ging is associated with a metabolic decline characterized by the development of changes in fat distribution, obesity, and insulin resistance (1-3). All these metabolic alterations are associated with a variety of age-related diseases that subsequently result in increased mortality (4 -9). It has been recently demonstrated that leptin, a 16-kDa fat-derived peptide, can modulate many of the metabolic alterations characteristic of aging (10 -12). Chronic administration of leptin decreases food intake and induces reduction in fat mass (FM) and visceral fat (VF), with a parallel significant improvement in hepatic and peripheral insulin action (10 -14). This finding suggests that alterations in leptin action may play a role in the metabolic phenotype of aging. Indeed, the dramatic increase in plasma leptin levels in aging animal models and in humans suggests a leptinresistant state (15-18). Although the increase in plasma leptin concentration in aging may be partially attributed to the development of obesity (which is associated with leptin resistance [19]), the increase in plasma leptin level during aging is often disproportionate to the increase in the amount of fat (16 -19). We therefore hypothesize that aging per se is associated with a failure in leptin's action, independent of obesity or changes in body fat distribution. Thus, leptin resistance of aging may represent a perpetuating factor in developing and maintaining obesity and its clinical consequences.Because aging is frequently associated with obesity, it is difficult to identify whether leptin failure is due to obesity, the process of aging per se, or both. To overcome this difficulty, we used caloric restriction throughout aging in a rodent model and prevented the typical age-related changes in body composition. We reasoned that aging rats would remain leptin resistant even when kept relatively lean and "metabolically young" by calorie restriction. RESEARCH DESIGN AND METHODS Animals.A total of 36 male Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA) were housed in individual cages and subjected to a standard light (6:00 A.M. to 6:00 P.M) to dark (6:00 P.M. to 6:0...
Abdominal obesity has been linked to the development of insulin resistance and Type 2 diabetes mellitus (DM2). By surgical removal of visceral fat (VF) in a variety of rodent models, we prevented insulin resistance and glucose intolerance, establishing a cause-effect relationship between VF and the metabolic syndrome. To characterize the biological differences between visceral and peripheral fat depots, we obtained perirenal visceral (VF) and subcutaneous (SC) fat from 5 young rats. We extracted mRNA from the fat tissue and performed gene array hybridization using Affymetrix technology with a platform containing 9 000 genes. Out of the 1 660 genes that were expressed in fat tissue, 297 (17.9 %) genes show a two-fold or higher difference in their expression between the two tissues. We present the 20 genes whose expression is higher in VF fat (by 3 - 7 fold) and the 20 genes whose expression is higher in SC fat (by 3 - 150 fold), many of which are predominantly involved in glucose homeostasis, insulin action, and lipid metabolism. We confirmed the findings of gene array expression and quantified the changes in expression in VF of genes involved in insulin resistance (PPARgamma leptin) and its syndrome (angiotensinogen and plasminogen activating inhibitor-1, PAI-1) by real-time PCR (qRT-PCR) technology. Finally, we demonstrated increased expression of resistin in VF by around 12-fold and adiponectin by around 4-fold, peptides that were not part of the gene expression platform. These results indicate that visceral fat and subcutaneous fat are biologically distinct.
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