Sympathetic denervation does not prevent a reduction in fat pad size of rats or mice treated with peripherally administered leptin

Abstract

. Sympathetic denervation does not prevent a reduction in fat pad size of rats or mice treated with peripherally administered leptin. Am J Physiol Regul Integr Comp Physiol 289: R92-R102, 2005; doi:10.1152/ajpregu.00858.2004.-Leptin increases sympathetic nervous system (SNS) activity in brown adipose tissue and renal nerves. Experiments described here tested whether SNS innervation is required for peripheral, physiological concentrations of leptin to reduce body fat. In experiment 1, one epididymal (EPI) fat pad was sympathectomized by local injection of 6-hydroxydopamine (6OHDA) in C57BL/6 mice that were then infused for 13 days with PBS or 10 g leptin/day from an intraperitoneal miniosmotic pump. Surprisingly, EPI denervation increased total body fat of PBS-infused mice but leptin decreased the size of both injected and noninjected EPI pads in 6OHDA mice. Experiment 2 was identical except for the use of male Sprague-Dawley rats that were infused with 50 g leptin/day. Leptin had little effect on EPI weight or norepinephrine (NE) content, but denervation of one EPI pad decreased the effect of leptin on intact EPI, inguinal and retroperitoneal (RP) fat and increased the size of the mesenteric fat pad. Experiment 3 included groups in which either one EPI or one RP pad was denervated. RP denervation reduced RP NE content but did not prevent a leptin-induced reduction in fat pad mass. Therefore, the SNS is not required for low doses of leptin to reduce body fat. EPI denervation significantly increased adipocyte number in contralateral EPI and RP fat pads and this was prevented by leptin. These changes in intact pads of rats with one denervated fat pad imply communication between fat depots and suggest that both leptin and the SNS regulate the size of individual depots. peripheral leptin infusion; norepinephrine; body weight IT IS WELL ESTABLISHED THAT administration of leptin to experimental animals results in a selective decrease in body fat mass while protecting lean body mass (24). A similar response has been observed in obese humans on a weight-reducing diet and receiving daily injections of leptin (26). The loss of body fat may be accompanied by hypophagia (18) but can occur in the absence of any sustained inhibition of food intake if low doses of leptin are infused peripherally into wild-type mice (4, 24). The mechanisms responsible for this specific reduction in body fat by physiological concentrations of leptin have not been fully elucidated. Leptin inhibits adipose tissue fatty acid synthesis (6, 21) and this is associated with a downregulation of expression of transcription factors and enzymes that promote lipogenesis (37,46). In addition, in vivo and in vitro studies have shown that very high concentrations of leptin promote lipolysis from adipocytes in wild-type mice (15) and rats (16), whereas physiological concentrations of leptin (10 ng/ml) have no effect on the lipolytic rate in isolated adipocytes (16). The lipolysis that is induced by leptin is unusual because a simultaneous stimulation of fat cel...

Effects of central or peripheral leptin administration on norepinephrine turnover in defined fat depots

“…In addition, leptin and pair feeding had opposing effects on NETO in RP fat from the centrally infused animals. Because the size of all white fat depots except MES decreased in both the centrally leptininfused and pair-fed animals in experiment 3, these results indicate that leptin does not depend on the SNS to reduce the size of all fat depots, consistent with the results of a study in which rats with one sympathetically denervated fat pad were infused with leptin (34). The results from experiment 2 also support this conclusion because peripherally infused leptin caused a significant decrease in the size of the MES tissue, whereas ING fat was the only depot to show even a tendency for an increase in NETO.…”

“…Few in vivo studies have examined the effect of leptin on the activity of sympathetic nerves in white fat depots (7,30,34), and, to our knowledge, a comparison of the effects of peripheral and central leptin infusion on NETO in individual fat depots has not previously been reported. We found that, regardless of the route of administration, leptin did not cause a uniform NETO response among the fat depots measured and that leptin decreased fat pad size independently of changes in NETO in several fat depots.…”

“…Previously, we attempted to determine the importance of sympathetic innervation of white fat in mediating leptin-induced changes in body fat mass by chemically sympathectomizing one fat pad in leptin-treated mice or rats (34). The outcome of this study was complicated by the finding that sympathectomy of one fat pad influenced both the norepinephrine (NE) content and leptin responsiveness of other neurally intact fat pads in the same animal.…”

Neural control of white, beige and brown adipocytes

“…44 In addition, DMH NPY knockdown increased the gene expression of the 'thermogenic program' (that is, PPARγ and Pgc-1α mRNA) in IWAT 44 ; DWAT was not assayed. To demonstrate that this effect was dependent on the SNS innervation of WAT, they used our specific, unilateral sympathetic denervation model, [45][46][47][48] where one IWAT depot received intra-WAT injections of the noradrenergic toxin 6-hydroxy-dopamine (6-OHDA) and its within-animal contralateral IWAT mate received vehicle control injections. [45][46][47][48] In the neurally intact IWAT pads of DMH NPY knockdown rats receiving intra-WAT vehicle injections, NE content (often a surrogate used for sympathetic drive, but not a replacement for NE turnover) was significantly increased compared with that of separate control rats receiving DMH injection of the scrambled shRNA.…”

Thematic review series: Adipocyte Biology. Sympathetic and sensory innervation of white adipose tissue

“…For example, fasting-induced decreases in WAT mass in laboratory rats, cats, rabbits, and dogs (110)(111)(112)(113)(114) are blocked, by surgical denervation, as is estradiol-induced decreases in WAT mass of ovariectomized rats (115) and the SD-induced decreases in WAT mass of Siberian hamsters (44,116,117). The lipidmobilizing effects of physiological doses of leptin given peripherally, however, are not blocked by WAT sympathetic denervation in laboratory rats (53).…”