Abstract
Hyperleptinemia causes disappearance of body fat without a rise in free fatty acids (FFA) or ketones, suggesting that leptin can deplete adipocytes of fat without releasing FFA. To test this, we measured FFA and glycerol released from adipocytes obtained from normal lean Zucker diabetic fatty rats (+/+) and incubated for 0, 3, 6, or 24 h in either 20 ng/ml recombinant leptin or 100 nM norepinephrine (NE). Whereas NE increased both FFA and glycerol release from adipocytes of +/+ rats, leptin increased glycerol release in +/+ adipocytes without a parallel increase in FFA release. In adipocytes of obese Zucker diabetic fatty rats (fa/fa) with defective leptin receptors, NE increased both FFA and glycerol release, but leptin had no effect on either. Leptin significantly lowered the mRNA of leptin and fatty acid synthase of adipocytes (FAS) (p < 0.05), and up-regulated the mRNA of peroxisome proliferator-activated receptor (PPAR)-alpha, carnitine palmitoyl transferase-1, (CPT-1), and acyl CoA oxidase (ACO) (p < 0.05). NE (100 nM) also lowered leptin mRNA (p < 0.05) but did not affect FAS, PPARalpha, ACO, or CPT-1 expression. We conclude that in normal adipocytes leptin directly decreases FAS expression, increases PPARalpha and the enzymes of FFA oxidation, and stimulates a novel form of lipolysis in which glycerol is released without a proportional release of FFA.
Highlights
IntroductionMost workers in the field believe that leptin acts largely, if not exclusively, via centers in the hypothalamus, suppressing appetite by inhibiting orexic factors such as neuropeptide Y [5] and by increasing thermogenesis via sympathetic innervation of brown adipose tissue [6]
From the Gifford Laboratories, Center for Diabetes Research and the Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235 and the Veterans Administration Medical Center, Dallas, Texas 75216
If the fat depletion caused by hyperleptinemia is, caused by norepinephrine through stimulation of sympathetic centers in the hypothalamus, it would be accompanied by a concomitant increase in plasma free fatty acids (FFA) levels [9], which did not occur in the hyperleptinemic rats
Summary
Most workers in the field believe that leptin acts largely, if not exclusively, via centers in the hypothalamus, suppressing appetite by inhibiting orexic factors such as neuropeptide Y [5] and by increasing thermogenesis via sympathetic innervation of brown adipose tissue [6] It seemed possible, that the disappearance of the fat of white adipocytes might be the result of leptin-induced, adrenergically mediated activation of lipolysis. If the fat depletion caused by hyperleptinemia is, caused by norepinephrine through stimulation of sympathetic centers in the hypothalamus, it would be accompanied by a concomitant increase in plasma FFA levels [9], which did not occur in the hyperleptinemic rats For these reasons, we suspected that the fat loss of hyperleptinemia involved a novel type of leptin-mediated lipolysis that was independent of catecholamines.
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