Selective Up-regulation of Fatty Acid Uptake by Adipocytes Characterizes Both Genetic and Diet-induced Obesity in Rodents

Abstract

Long chain fatty acid transport is selectively up-regulated in adipocytes of Zucker fatty rats, diverting fatty acids from sites of oxidation toward storage in adipose tissue. To determine whether this is a general feature of obesity, we studied [ 3 H]oleate uptake by adipocytes and hepatocytes from 1) homozygous male obese (ob), diabetic (db), fat (fat), and tubby (tub) mice and from 2) male Harlan Sprague-Dawley rats fed for 7 weeks a diet containing 55% of calories from fat. V max and K m were compared with controls of the appropriate background strain (C57BL/6J or C57BLKS) or diet (13% of calories from fat). V max for adipocyte fatty acid uptake was increased 5-6-fold in ob, db, fat, and tub mice versus controls (p < 0.001), whereas no differences were seen in the corresponding hepatocytes. Similar changes occurred in fat-fed rats. Of three membrane fatty acid transporters expressed in adipocytes, plasma membrane fatty acid-binding protein mRNA was increased 9 -11-fold in ob and db, which lack a competent leptin/leptin receptor system, but was not increased in fat and tub, i.e. in strains with normal leptin signaling capability; fatty acid translocase mRNA was increased 2.2-6.5-fold in tub, ob, and fat adipocytes, but not in db adipocytes; and only marginal changes in fatty acid transport protein 1 mRNA were found in any of the mutant strains. Adipocyte fatty acid uptake is generally increased in murine obesity models, but up-regulation of individual transporters depends on the specific pathophysiology. Leptin may normally down-regulate expression of plasma membrane fatty acid binding protein.In normal man and most mammalian species, body weight is maintained within narrow limits through regulation of both caloric intake and energy expenditure (1, 2). If caloric intake persistently exceeds energy expenditure, obesity is an inevitable consequence. However, there are obvious differences in the tendency to obesity among individuals with seemingly equivalent caloric intake and similar degrees of physical activity (3). Likewise, there are differences among rat strains in the propensity to develop obesity on high fat diets (4). Finally, a number of single-gene mutations that lead to obesity in mice and rats have been identified and cloned (5-13), leading in several instances to elucidation of the mechanisms underlying phenotypic expression. Studies in these animal models and in obese humans have led to the concepts of energy efficiency and of nutrient partitioning as being important physiological mechanisms underlying individual or strain differences in the propensity to become obese (1,14,15).Individuals with high energy efficiency require fewer calories to meet basal metabolic needs and accomplish a given level of physical work. Thus, on a given caloric intake, more calories are, in essence, left over, and are stored as fat. Individuals with low energy efficiency utilize more of their caloric intake for basal metabolism and physical work, leaving fewer calories for storage as fat. The factors responsible for dif...

Differences in adipocyte long chain fatty acid uptake in Osborne–Mendel and S5B/Pl rats in response to high-fat diets

“…6,7,9 The former suggestion was supported by strong correlations between plasma insulin and the V max for adipocyte LCFA uptake in obese and nonobese humans. 8 While leptin is an insulin counter-regulatory hormone in some settings, 50 in others its effects parallel those of insulin.…”

“…22 Fatty acid uptake studies Long chain fatty acid uptake kinetics by adipocyte suspensions were measured by rapid filtration using tracer amounts of [ 3 H]-oleic acid (OA). 3,6 As previously, 3,[6][7][8][9]23 data for OA uptake were best fitted by the sum of a saturable plus a nonsaturable function of the unbound OA concentration in the incubation medium, of the form:…”

“…Uptake occurs via two discrete processes: regulatable, protein-mediated, facilitated transport and passive flip-flop (diffusion) across the plasma membrane. [3][4][5] We have demonstrated several fold upregulation of saturable LCFA uptake in adipocytes from single-gene obesity models such as the Zucker rat, 6 ob, db, fat and tubby mouse, 7 and in dietary models of obesity in both rats and mice. 7 A similar upregulation of LCFA uptake occurs in omental adipocytes from obese patients undergoing bariatric surgery.…”

“…[3][4][5] We have demonstrated several fold upregulation of saturable LCFA uptake in adipocytes from single-gene obesity models such as the Zucker rat, 6 ob, db, fat and tubby mouse, 7 and in dietary models of obesity in both rats and mice. 7 A similar upregulation of LCFA uptake occurs in omental adipocytes from obese patients undergoing bariatric surgery. 8 Upregulation of adipocyte LCFA uptake precedes onset of overt obesity in weanling Zucker rats, 6 and downregulation of adipocyte LCFA uptake precedes weight loss during leptin administration to ob mice, 9 suggesting that regulation of adipocyte LCFA uptake is a key control point for body adiposity.…”

Long-chain fatty acid uptake is upregulated in omental adipocytes from patients undergoing bariatric surgery for obesity

“…1,2 We have also shown that obesity resulting from a variety of causes (eg genetic, dietary) in several rodent species is associated with the tissue-specific upregulation of saturable LCFA uptake by adipocytes, but not by hepatocytes or cardiac myocytes. 3,4 These findings suggest (1) that the selective upregulation of adipocyte LCFA uptake in obesity alters LCFA partitioning, diverting LCFA away from tissues where they would be consumed as fuel to adipose tissue, where they are stored as triglycerides; and (2) that the increase in saturable LCFA uptake reflects upregulation of specific membrane transport process(es). In animal models such as the ob/ob mouse, insulin appears to be an important upregulator and leptin a key downregulator of adipocyte LCFA uptake.…”