Removal of Visceral Fat Prevents Insulin Resistance and Glucose Intolerance of Aging

Abstract

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...

Hypothalamic pro-opiomelanocortin gene delivery ameliorates obesity and glucose intolerance in aged rats

“…Aged F344/BN rats are associated with insulin resistance and glucose intolerance, as shown in several previous reports [15,18,44]. In the present study, we also observed impaired glucose tolerance, as indicated by the elevated blood glucose levels after glucose loading in the aged obese F344/BN rats.…”

“…This increase in body weight with age is a major risk factor for insulin resistance, diabetes and ath-erosclerotic cardiovascular disease [15]. Aged mice and rats are associated with reduced hypothalamic Pomc expression [12], and the induction of Pomc by exogenous leptin is impaired with ageing [16].…”

Diabetes: mellitus or lipidus?

“…Because of the non-availability of fat substrate, muscle insulin responsiveness was very high but could be reversed by fat implantation. Similarly, the surgical excision of visceral fat in ageing Zucker diabetic and FBN insulin-resistant rats markedly improved the peripheral and hepatic insulin action [98]. In high fat fed rats, treatment with another TZD, BRL49653, reduced systemic NEFA and pronouncedly improved insulin action and glucoregulation [99].…”

Accretion of visceral fat and hepatic insulin resistance in pregnant rats

“…The mesenteric fat was left intact because of the high morbidity associated with its removal. The amount of VF removed was ϳ10 -20% of total fat mass (13). For sham operations, the abdominal cavity was incised, and the VF was mobilized from its surrounding tissues but not removed.…”

“…Central obesity is considered to be an essential component of the metabolic syndrome (1), and increased visceral fat is associated with decreases in peripheral and hepatic insulin sensitivity (5,9,14). Surgical extraction of visceral fat has been shown to reverse insulin resistance in young obese and old male rodents (13) and to delay the onset of diabetes in Zucker rats, a model of progressive obesity and diabetes (13). During pregnancy, maternal body fat increases on average Ͼ3 kg (19), with indirect evidence to suggest that visceral fat increases in particular (21).…”