Diseases of liporegulation: new perspective on obesity and related disorders

Abstract

Obesity‐related diseases now threaten to reach epidemic proportions in the United States. Here we review in a rodent model of genetic obesity, the fa/fa Zucker diabetic fatty (ZDF) rat, the mechanisms involved in the most common complications of diet‐induced human obesity, i.e., noninsulin‐dependent diabetes mellitus, and myocardial dysfunction. In ZDF rats, hyperphagia leads to hyperinsulinemia, which up‐regulates transcription factors that stimulate lipogene‐sis. This causes ectopic deposition of triacylglycerol in nonadipocytes, providing fatty acid (FA) substrate for damaging pathways of nonoxidative metabolism, such as ceramide synthesis. In β cells and myocardium, the resulting functional impairment and apoptosis cause diabetes and cardiomyopathy. Interventions that lower ectopic lipid accumulation or block nonoxidative metabolism of FA and ceramide formation completely prevent these complications. Given the evidence for a similar etiology for the complications of human obesity, it would be appropriate to develop strategies to avert the predicted epidemic of lipotoxic disorders.—Unger, R. H., Orci, L. Diseases of lipid overflow: new perspective on obesity and related disorders. FASEB J. 15, 312‐321 (2001)

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

“…[56][57][58] As depicted in Figure 3, the earlier demonstrations that leptin can act directly on skeletal muscle, specifically via the long form of the leptin receptor (ObRb), to stimulate glucose utilization in a PI3K-dependent manner 59,60 and lipid oxidation via the activation of AMP-activated protein kinase (AMPK) leading to inhibition of ACCs 58,61 prompted us to investigate whether leptin could also exert direct control on thermogenesis in skeletal muscle. Using a method that involves repeated measurements of O 2 consumption in intact muscle perifused ex vivo with Krebs-Ringer buffer, we found that leptin could directly stimulate thermogenesis in skeletal muscle via ObRb, 62 and that this thermogenic effect of leptin, which requires PI3K activity (since it is inhibited by wortmannin), is potentiated by insulin, a potent activator of PI3K.…”

“…70 Furthermore, this 'dependency' interaction between these two substrates and thermogenesis is well recognized at the whole-body level, and is attributed to activation of a neuroendocrine network (comprising insulin, leptin and the sympathoadrenal system), which plays a pivotal role in several overlapping regulatory systems: that of blood glucose, body temperature, body weight and more recently intramyocellular lipids. [56][57][58] Interference with any of these hormones or their actions leads to major impairments in all these overlapping regulatory functions. In particular, the absence of functional leptin (eg, in the ob/ob mouse) or dysfunctional leptin signaling (eg, in db/db mice or fa/fa rats) leads not only to impairments in thermogenesis that contribute to obesity, but also to hyperglycemia and excessive accumulation of lipids in nonadipose tissues, including the skeletal muscle.…”

“…In particular, the absence of functional leptin (eg, in the ob/ob mouse) or dysfunctional leptin signaling (eg, in db/db mice or fa/fa rats) leads not only to impairments in thermogenesis that contribute to obesity, but also to hyperglycemia and excessive accumulation of lipids in nonadipose tissues, including the skeletal muscle. [56][57][58] The fact that, in these animal models, the stimulation of thermogenesis induced by leptin replacement 58 or by treatment with b3 adrenoceptor agonists 75 improves insulin sensitivity and reduces ectopic fat storage at low-dose levels or over time periods that do not affect body weight strongly suggests that impaired thermogenesis might be an early event in the dysregulation of blood glucose and intramyocellular lipids. To date, however, the molecular mechanisms underlying thermogenesis in tissues other than the brown adipose tissue remains elusive, amid continuing controversies concerning the physiological roles of UCP2 and UCP3 (homologs of UCP1) as effectors of skeletal muscle thermogenesis.…”

Glucose-Dependent Insulinotropic Polypeptide Enhances Adipocyte Development and Glucose Uptake in Part Through Akt Activation

“…Insulin has been shown to be a potent stimulator of lipogenesis, 5 and overnutrition causes secondary hyperinsulinemia and subsequent adipocyte hypertrophy. 6 Previous studies have shown that the selective disruption of the insulin receptor (IR) gene in fat cells resulted in mice with a low fat mass and that the mice were protected against obesity and obesity-related glucose intolerance. 7…”

The equivocal metabolic response to endotoxaemia in type 2 diabetic and obese ZDF rats

“…It is well known that obesity associated with type 2 diabetes affects nutritional status [18]. However, the literature contains few data on the metabolic response to stress in obese and diabetic patients.…”