Energy intake-independent modulation of triglyceride metabolism by glucocorticoids in the rat

This study aimed to dissociate the peripheral effects of adrenalectomy (ADX) on triglyceride (TG) metabolism from those it exerts centrally on energy intake and to determine the impact of diet composition therein. Rats were fed either rodent chow or a diet high in sucrose and fat (HSF) and were adrenalectomized or left intact and pair fed to the ADX animals. Liver TG content, an index of hepatic TG production, was not affected by ADX, but was increased twofold by the HSF diet. ADX decreased the rate of hepatic TG secretion by 41% in chow-fed but not in HSF-fed animals. Triglyceridemia and postheparin plasma lipase activities remained largely unchanged by treatments. ADX decreased insulinemia fivefold in chow-fed rats, but less so in HSF-fed animals. Likewise, subcutaneous and visceral adipose depots were 40-60% smaller in ADX than in intact pair-fed rats given chow, but the effect of ADX was dampened by consumption of the HSF diet. Although smaller, adipose tissues of ADX rats maintained a higher activity of lipoprotein lipase (LPL) than those of intact pair-fed rats, whereas muscle LPL was decreased. The study confirms that in the presence of reduced energy intake, corticosterone contributes to the maintenance of adipose stores and that the consequences of its absence tend to be attenuated when a high-energy diet is fed. The study further shows that, contrary to ad libitum feeding conditions, most determinants of TG metabolism, such as hepatic TG stores, triglyceridemia, postheparin plasma LPL, and adipose tissue LPL, are minimally affected by glucocorticoids when consumption of a high-energy diet is restricted, suggesting that glucocorticoids affect TG metabolism mostly indirectly through their central action on ingestive behavior.     

HPA-axis responses during experimental colitis in the rat

We investigated the responses of the hypothalamic-pituitary-adrenal (HPA) axis during experimental colitis induced by intracolonic administration of 2,4,6-trinitrobenzenesulfonic acid in the rat. On days 3 and 7 after induction of colitis, the corticotropin-releasing hormone (CRH) mRNA level in the parvocellular paraventricular nucleus (pPVN) of the hypothalamus was reduced, the plasma ACTH level remained at the basal level, and the plasma corticosterone (Cort) level was high. Induction of colitis on day 3 after adrenalectomy with Cort pellet replacement (ADX + Cort) resulted in a marked increase in CRH mRNA on day 7 after induction of colitis compared with noncolitic ADX + Cort animals. Pair feeding to match the food intake of the colitic animals resulted in no significant change in CRH mRNA in the pPVN, plasma ACTH, and Cort compared with healthy control animals. These findings indicated that CRH mRNA expression in the pPVN was inhibited by glucocorticoid feedback during this experimental colitis, and the decrease in food intake during colitis was not simply responsible for the expression of CRH mRNA. It is inferred that the HPA axis including the CRH level in the pPVN is altered in patients with inflammatory bowel disease.     

Sleep deprivation can inhibit adult hippocampal neurogenesis independent of adrenal stress hormones

Sleep deprivation (SD) can suppress cell proliferation in the hippocampal dentate gyrus of adult male rodents, suggesting that sleep may contribute to hippocampal functions by promoting neurogenesis. However, suppression of cell proliferation in rats by the platform-over-water SD method has been attributed to elevated corticosterone (Cort), a potent inhibitor of cell proliferation and nonspecific correlate of this procedure. We report here results that do not support this conclusion. Intact and adrenalectomized (ADX) male rats were subjected to a 96-h SD using multiple- and single-platform methods. New cells were identified by immunoreactivity for 5-bromo-2'-deoxyuridine (BrdU) or Ki67 and new neurons by immunoreactivity for BrdU and doublecortin. EEG recordings confirmed a 95% deprivation of rapid eye movement (REM) sleep and a 40% decrease of non-REM sleep. Cell proliferation in the dentate gyrus was suppressed by up to 50% in sleep-deprived rats relative to apparatus control or home cage control rats. This effect was also observed in ADX rats receiving continuous low-dose Cort replacement via subcutaneous minipumps but not in ADX rats receiving Cort replacement via drinking water. In these latter rats, Cort intake via water was reduced by 60% during SD; upregulation of cell proliferation by reduced Cort intake may obscure inhibitory effects of sleep loss on cell proliferation. SD had no effect on the percentage of new cells expressing a neuronal phenotype. These results demonstrate that the Cort replacement method is critical for detecting an effect of SD on cell proliferation and support a significant role for sleep in adult neurogenesis.     

Effect of the exercise-induced increase in glucocorticoids on endurance in the rat

To investigate the effect of the increase in glucocorticoids during exercise on endurance, rats were either sham operated (SO) or adrenalectomized. All adrenalectomized rats were given a subcutaneously implanted corticosterone pellet at the time of adrenalectomy. Adrenalectomized rats were injected with corticosterone (ADX Cort) or corn oil (ADX) 5 min before exercise. Rats were killed at rest or after running on a treadmill (21 m/min, 15% grade) until exhaustion. SO rats ran 138 +/- 6 min compared with 114 +/- 9 min for ADX Cort and 89 +/- 8 min for ADX. All differences in run times were significant (P less than 0.05). Corticosterone levels were similar in exhausted SO and ADX Cort groups. ADX exhausted rats had corticosterone levels similar to resting values in SO and ADX rats. Inhibition of the rise in glucocorticoids during exercise had no effect on liver glycogen, liver adenosine 3',5'-cyclic monophosphate, plasma insulin, blood glucose, lactate, glycerol, or 3-hydroxybutyrate, plasma norepinephrine, or red quadriceps and soleus glycogen. Plasma free fatty acids were significantly depressed at exhaustion in ADX rats compared with SO. These data show that glucocorticoids exert effects within the time frame of a prolonged exercise bout and play a role in increasing endurance.     

Central Exendin‐4 Infusion Reduces Body Weight without Altering Plasma Leptin in (fa/fa) Zucker Rats

Objective: To investigate whether chronic administration of the long‐acting glucagon‐like peptide‐1 receptor agonist exendin‐4 can elicit sustained reductions in food intake and body weight and whether its actions require an intact leptin system. Research Methods and Procedures: Male lean and obese Zucker (fa/fa) rats were infused intracerebroventricularly with exendin‐4 using osmotic minipumps for 8 days. Results: Exendin‐4 reduced body weight in both lean and obese Zucker rats, maximum suppression being reached on Day 5 in obese (8%) and Day 7 in lean (16%) rats. However, epididymal white adipose tissue weight was not reduced, and only in lean rats was there a reduction in plasma leptin concentration. Food intake was maximally suppressed (by 81%) on Day 3 in obese rats but was reduced by only 18% on Day 8. Similarly, in lean rats food intake was maximally reduced (by 93%) on Day 4 of treatment and by 45% on Day 8. Brown adipose tissue temperature was reduced from Days 2 to 4. Plasma corticosterone was elevated by 76% in lean but by only 28% in obese rats. Discussion: Chronic exendin‐4 treatment reduced body weight in both obese and lean Zucker rats by reducing food intake: metabolic rate was apparently suppressed. These effects did not require an intact leptin system. Neither does the absence of an intact leptin system sensitize animals to exendin‐4. Partial tolerance to the anorectic effect of exendin‐4 in lean rats may have been due to elevated plasma corticosterone and depressed plasma leptin levels, but other counter‐regulatory mechanisms seem to play a role in obese Zucker rats.     

Leptin extends the anorectic effects of chronic PYY(3-36) administration in ad libitum-fed rats

Acute administration of peptide YY(3-36) [PYY(3-36)] results in a reduction in food intake in several different vertebrates. However, long-term continuous administration of PYY(3-36) causes only a transient reduction in food intake, thus potentially limiting its therapeutic efficacy. We hypothesized that a fall in leptin levels associated with reduced food intake could contribute to the transient anorectic effects of continuous PYY(3-36) infusion and thus that leptin replacement might prolong the anorectic effects of PYY(3-36). Seven-day administration of 100 microg x kg body wt(-1) x day(-1) PYY(3-36) using osmotic minipumps caused a significant reduction in food intake of ad libitum-fed rats, but only for the first 2 days postimplantation. Circulating levels of leptin were reduced 1 day following continuous infusion of PYY(3-36), and combined leptin infusion at a dose of leptin that had no anorectic effects on its own (100 microg x kg body wt(-1) x day(-1)) prolonged the anorectic actions of PYY(3-36) in ad libitum-fed rats for up to 6 days postimplantation and yielded reduced weight gain compared with either peptide alone. The inhibitory effects of 100 microg x kg body wt(-1) x day(-1) PYY(3-36) on food intake were absent in rats refed after a 24-h fast and substantially reduced at a dose of 1,000 microg x kg body wt(-1) x day(-1) PYY(3-36). Leptin replacement was unable to recover the anorectic effects of PYY(3-36) in fasted rats. Our results suggest that an acute fall in leptin levels is not solely responsible for limiting duration of action of chronic PYY(3-36) infusion, yet chronic coadministration of a subanorectic dose of leptin can extend the anorectic effects of PYY(3-36).     

Nicotine infusion alters leptin and uncoupling protein 1 mRNA expression in adipose tissues of rats

We attempted to clarify whether leptin and uncoupling protein 1 (UCP1) are involved in the action of nicotine on the energy balance. Male Wistar rats were infused subcutaneously with nicotine (12 mg x kg(-1) x day(-1)) for 4 or 14 days. At the end of the 4-day period, the plasma concentrations of leptin of the nicotine-treated and pair-fed rats were lower than those of the freely fed rats, although the levels of leptin mRNA expression in various white adipose tissues did not differ among the three groups. At the end of the 14-day nicotine infusion period, plasma concentrations of leptin were higher, and leptin mRNA expression in the omentum and epididymal and retroperitoneal adipose tissues was stronger in the nicotine-treated rats than in the pair-fed and freely fed rats. UCP1 mRNA expression in the brown adipose tissue of nicotine-treated was stronger than that of the pair-fed rats. These results suggest that continuous nicotine infusion differentially affects the synthesis and secretion of leptin according to the duration of infusion and stimulates UCP1 mRNA expression, probably in a manner independent of leptin.     

Acylation-stimulating protein/C5L2-neutralizing antibodies alter triglyceride metabolism in vitro and in vivo

Acylation-stimulating protein (ASP), a lipogenic hormone, stimulates triglyceride (TG) synthesis and glucose transport upon activation of C5L2, a G protein-coupled receptor. ASP-deficient mice have reduced adipose tissue mass due to increased energy expenditure despite increased food intake. The objective of this study was to evaluate the blocking of ASP-C5L2 interaction via neutralizing antibodies (anti-ASP and anti-C5L2-L1 against C5L2 extracellular loop 1). In vitro, anti-ASP and anti-C5L2-L1 blocked ASP binding to C5L2 and efficiently inhibited ASP stimulation of TG synthesis and glucose transport. In vivo, neither anti-ASP nor anti-C5L2-L1 altered body weight, adipose tissue mass, food intake, or hormone levels (insulin, leptin, and adiponectin), but they did induce a significant delay in TG clearance [P < 0.0001, 2-way repeated-measures (RM) ANOVA] and NEFA clearance (P < 0.0001, 2-way RM ANOVA) after a fat load. After treatment with either anti-ASP or anti-C5L2-L1 antibody there was no change in adipose tissue AMPK activity, but neutralizing antibodies decreased perirenal TG mass (-38.4% anti-ASP, -18.8% anti-C5L2, P < 0.01-0.001) and perirenal LPL activity (-75.6% anti-ASP, -72.5% anti-C5L2, P < 0.05). In liver, anti-C5L2-L1 decreased TG mass (-42.8%, P < 0.05), whereas anti-ASP increased AMPK activity (+34.6%, P < 0.001). In the muscle, anti-C5L2-L1 significantly increased TG mass (+128.0%, P < 0.05), LPL activity (+226.1%, P < 0.001), and AMPK activity (+71.1%, P < 0.01). In addition, anti-ASP increased LPL activity (+164.4, P < 0.05) and AMPK activity (+53.9%, P < 0.05) in muscle. ASP/C5L2-neutralizing antibodies effectively block ASP-C5L2 interaction, altering lipid distribution and energy utilization.     

有氧运动同时补充玉米肽对肥胖大鼠脂肪分解关键酶的影响

目的：研究有氧运动同时补充玉米肽对高脂饮食诱导的肥胖大鼠减脂的作用及其与脂肪分解关键酶甘油三酯脂肪酶（ATGL）和脂蛋白酯酶（LPL）关系。方法：4周龄健康雄性SD大鼠150只,体重160~180 g,随机选取15只作为普通膳食不运动组,给予普通饲料喂养。剩余135只大鼠进行8周的高脂饲料喂养建立肥胖大鼠模型,以体重超过普通膳食不运动组大鼠平均体重的20%作为肥胖大鼠建模成功的标准。将建模成功的肥胖大鼠40只随机分为5组（n=8）：肥胖对照组、酪蛋白组、玉米肽组、运动组和运动+玉米肽组。除酪蛋白组、玉米肽组喂养自制饲料外,其余各组均用普通饲料喂养,运动组每天进行15 m/min,持续时间60 min的跑台运动,每周6天。4周运动和玉米肽干预后取血,检测大鼠血浆中TG、TC、HDL、LDL的含量;取大鼠肾周、附睾脂肪和肝,检测肾周和附睾脂肪的重量,Western blot检测大鼠肝ATGL、脂肪LPL的蛋白表达水平。结果：与肥胖对照组大鼠相比：①运动组、运动+玉米肽组大鼠的体重、附睾和肾周脂肪含量明显降低（P<0.05）,且运动+玉米肽组比运动组下降得更明显（P<0.05）,而其它组大鼠无显著差异。②运动组大鼠血浆TG显著降低,运动+玉米肽组的血浆TG、TC显著降低（P<0.05）,其它组大鼠的TG、TC无显著差异;血浆HDL和LDL各组间均无显著性差异。③运动组和运动+玉米肽组大鼠的肝ATGL、脂肪组织LPL的蛋白水平明显增加（P<0.01）,且运动+玉米肽组比运动组的更显著（P<0.05）;其他两组无显著差异。结论：有氧运动、有氧运动同时补充玉米肽都可以明显降低大鼠的体脂和血脂水平,且后者的作用更强,这可能与其更显著地增加肥胖大鼠肝ATGL和脂肪LPL的蛋白水平有关。而仅仅补充玉米肽不能降低大鼠的体脂和血脂水平。     

Release of lipoprotein lipase to plasma by triacylglycerol emulsions. Comparison to the effect of heparin.

It was previously known that lipoprotein lipase (LPL) activity in plasma rises after infusion of a fat emulsion. To explore the mechanism we have compared the release of LPL by emulsion to that by heparin. After bolus injections of a fat emulsion (Intralipid) to rats, plasma LPL activity gradually rose 5-fold to a maximum at 6-8 min. During the same time the concentration of injected triacylglycerols (TG) decreased by about half. Hence, the time-course for plasma LPL activity was quite different from that for plasma TG. The disappearance of injected 125I-labelled bovine LPL from circulation was retarded by emulsion. This effect was more marked 30 min than 3 min after injection of the emulsion. The data indicate that the release of LPL into plasma is not solely due to binding of the lipase to the emulsion particles as such, but involves metabolism of the particles. Emulsion increased the fraction of labelled LPL found in adipose tissue, heart and the red muscle studied, but had no significant effect on the fraction found in liver. The effects of emulsion were quite different from those of heparin, which caused an immediate release of the lipase to plasma, decreased uptake of LPL in most extrahepatic tissues by 60-95%, and increased the fraction taken up in the liver.     

Response of leptin mRNA to 24-h food deprivation and refeeding is influenced by age in rats

To obtain an insight into the influence of aging on leptin gene expression, the responses of leptin mRNA in retroperitoneal and epididymal adipose tissues and plasma leptin concentrations to 24-h food deprivation and refeeding were examined in 2-, 10- and 24-month-old normal rats. The basal level of leptin gene expression in retroperitoneal adipose tissue was significantly higher in 10- and 24-month-old rats than that in 2-month-old rats, while the level in epididymal adipose tissue was highest in 10-month-old rats for all three age groups. The basal concentrations of plasma leptin was significantly higher in 10- and 24-month-old rats than those in 2-month-old rats. The 24-h food deprivation was followed by a significant reduction in leptin mRNA expression in both retorperitoneal and epididymal adipose tissues for all three age groups. The leptin gene expression was restored to control levels 24 h following refeeding in the 2- and 10-month-old rats, but failed to be restored in the 24-month-old rats. In addition, the time course of recovery for leptin mRNA expression by refeeding to the control levels differed between the retroperitoneal and the epididymal adipose tissue in 2- and 10-month-old rats. The concentrations of plasma leptin 24 h following refeeding were compatible with the leptin mRNA levels in adipose tissues in three age groups. These results suggest that the expression of the leptin gene in response to food-deprivation and refeeding is influenced by an animal's age and that this expression is different for different regions of white adipose tissue.     

Adrenalectomy Reduces Adiposity by Decreasing Feed Efficiency,Not Direct Effects on White Adipose Tissue

EDENS, N. K., A. MOSHIRFAR, G. M. POTTER, S. K. FRIED, AND T. W. CASTONGUAY. Adrenalectomy reduces adiposity by decreasing feed efficiency, not direct effects on white adipose tissue. Obes Res. Objective: This study was conducted to establish the effects of adrenalectomy (ADX) on adipose tissue metabolism in male Sprague—Dawley rats fed a standard chow diet. Research Methods and Procedures: The effects of adrenalectomy on adipose cell size, lipoprotein lipase activity, and basal and insulin-stimulated glucose conversion to lipid and lipolysis were measured. Results: ADX decreased body weight gain during the postoperative period in the absence of changes in food intake; feed efficiency was decreased significantly. ADX decreased adipocyte size by 30%. ADX increased adipocyte response to the effect of submaximal concentrations of insulin on lipid synthesis and lipolysis. ADX decreased maximally insulin-stimulated lipid synthesis, but this effect was accounted for by decreased adipocyte size. In contrast, ADX had no effect on maximally insulin-inhibited lipolysis. ADX did not affect heparin-releasable LPL. The small effect of ADX on residual extractable adipose tissue LPL activity was accounted for by decreased fat cell size. Discussion: ADX decreased adiposity in the absence of changes in food intake, lipoprotein lipase activity, and adipocyte lipid metabolism. The effect is best attributed to decreased feed efficiency.     

Physiological regulation of hypothalamic IL-1beta gene expression by leptin and glucocorticoids: implications for energy homeostasis

Interleukin-1beta (IL-1beta) is synthesized in a variety of tissues, including the hypothalamus, where it is implicated in the control of food intake. The current studies were undertaken to investigate whether hypothalamic IL-1beta gene expression is subject to physiological regulation by leptin and glucocorticoids (GCs), key hormones involved in energy homeostasis. Adrenalectomy (ADX) increased hypothalamic IL-1beta mRNA levels twofold, measured by real-time PCR (P < 0.05 vs. sham-operated controls), and this effect was blocked by subcutaneous infusion of a physiological dose of corticosterone. Conversely, hypothalamic IL-1beta mRNA levels were reduced by 30% in fa/fa (Zucker) rats, a model of genetic obesity caused by leptin receptor mutation (P = 0.01 vs. lean littermates), and the effect of ADX to increase hypothalamic IL-1beta mRNA levels in fa/fa rats (P = 0.02) is similar to that seen in normal animals. Moreover, fasting for 48 h (which lowers leptin and raises corticosterone levels) reduced hypothalamic IL-1beta mRNA levels by 30% (P = 0.02), and this decrease was fully reversed by refeeding for 12 h. Thus leptin and GCs exert opposing effects on hypothalamic IL-1beta gene expression, and corticosterone plays a physiological role to limit expression of this cytokine in both the presence and absence of intact leptin signaling. Consistent with this hypothesis, systemic leptin administration to normal rats (2 mg/kg ip) increased hypothalamic IL-1beta mRNA levels twofold (P < 0.05 vs. vehicle), an effect similar to that of ADX. These data support a model in which expression of hypothalamic IL-1beta is subject to opposing physiological regulation by corticosterone and leptin.     

Effect of chronic intermittent hypoxia on triglyceride uptake in different tissues

Chronic intermittent hypoxia (CIH) inhibits plasma lipoprotein clearance and adipose lipoprotein lipase (LPL) activity in association with upregulation of an LPL inhibitor angiopoietin-like protein 4 (Angptl4). We hypothesize that CIH inhibits triglyceride (TG) uptake via Angptl4 and that an anti-Angptl4-neutralizing antibody would abolish the effects of CIH. Male C57BL/6J mice were exposed to four weeks of CIH or intermittent air (IA) while treated with Ab (30 mg/kg ip once a week). TG clearance was assessed by [H³]triolein administration retroorbitally. CIH delayed TG clearance and suppressed TG uptake and LPL activity in all white adipose tissue depots, brown adipose tissue, and lungs, whereas heart, liver, and spleen were not affected. CD146+ CD11b− pulmonary microvascular endothelial cells were responsible for TG uptake in the lungs and its inhibition by CIH. Antibody to Angptl4 decreased plasma TG levels and increased TG clearance and uptake into adipose tissue and lungs in both control and CIH mice to a similar extent, but did not reverse the effects of CIH. The antibody reversed the effects of CIH on LPL in adipose tissue and lungs. In conclusion, CIH inactivates LPL by upregulating Angptl4, but inhibition of TG uptake occurs predominantly via an Angptl4/LPL-independent mechanism.     

Photoperiod regulates leptin sensitivity in field voles, Microtus agrestis

We have previously shown that cold-acclimated (8°C) male field voles (Microtus agrestis) transferred from short (SD, 8:16 h L:D) to long photoperiod (LD, 16:8 h L:D) exhibit increases in body mass, adiposity and food intake. To assess whether these increases were associated with decreased leptin sensitivity, we infused LD and SD voles with physiological doses of murine leptin (or saline) delivered peripherally for 7 days via mini-osmotic pumps. Measurements were made of body mass (weight-reducing effect of leptin), food intake (anorectic effect of leptin) and gene expression of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) (thermogenic effect of leptin). The SD animals were sensitive to the weight-reducing effects of leptin (mean body mass decrease of 1.2 g over 7 days) and appetite-reducing effect of leptin (mean food intake decrease of 2.5 g over 7 days), whereas LD voles were resistant to the hormone treatment. The switch from a leptin-sensitive to leptin-resistant state appears to act as a desensitisation mechanism that allows voles transferred from SD to LD to ignore elevated leptin levels generated by increased body fat and accumulate adipose tissue without stimulating compensatory changes opposing the weight gain. Neither SD nor LD voles responded to infusion of leptin by changes in BAT UCP1 gene expression, suggesting dissociation of anorectic and thermogenic effects of leptin, possibly related to chronic cold exposure. Our results indicate that cold-acclimated voles show photoperiod-regulated changes in leptin sensitivity and may provide an attractive model for elucidating molecular mechanisms of leptin resistance.     

Chylomicron metabolism in an animal model for hyperlipoproteinemia type I.

Mink homozygous for the mutation Pro214Leu in lipoprotein lipase (LPL) had only traces of LPL activity but amounts of LPL protein in their tissues similar to those of normal mink. In normal mink, lymph chylomicrons from rats given [3H]retinol (incorporated into retinyl esters, providing a core label) and [14C]oleic acid (incorporated mainly in triglycerides (TG)) were rapidly cleared from the circulation. In the homozygous mink, clearance was much retarded. The ratio of TG to core label in plasma did not decrease and much less [14C]oleic acid appeared in plasma. Still, half of the labeled material disappeared from the circulating blood within 30;-40 min and the calculated total turnover of TG in the hypertriglyceridemic mink was almost as large as in normal mink. The core label was distributed to the same tissues in hypertriglyceridemic mink as in normal mink. Half to two-thirds of the cleared core label was in the liver. The large difference was that in the hypertriglyceridemic mink, TG label (about 40% of the total amount removed) followed the core label to the liver and there was no preferential uptake of TG over core label in adipose or muscle tissue. In normal mink, only small amounts of TG label (<10%) appeared in the liver, while most was in adipose and muscle tissues. Apolipoprotein B-48 dominated in the accumulated TG-rich lipoproteins in blood of hypertriglyceridemic mink, even in fasted animals.     

Chronic Glucocorticoid Exposure-Induced Epididymal Adiposity Is Associated with Mitochondrial Dysfunction in White Adipose Tissue of Male C57BL/6J Mice

Prolonged and excessive glucocorticoids (GC) exposure resulted from Cushing''s syndrome or GC therapy develops central obesity. Moreover, mitochondria are crucial in adipose energy homeostasis. Thus, we tested the hypothesis that mitochondrial dysfunction may contribute to chronic GC exposure-induced epididymal adiposity in the present study. A total of thirty-six 5-week-old male C57BL/6J mice (∼20 g) were administrated with 100 µg/ml corticosterone (CORT) or vehicle through drinking water for 4 weeks. Chronic CORT exposure mildly decreased body weight without altering food and water intake in mice. The epididymal fat accumulation was increased, but adipocyte size was decreased by CORT. CORT also increased plasma CORT, insulin, leptin, and fibroblast growth factor 21 concentrations as measured by RIA or ELISA. Interestingly, CORT increased plasma levels of triacylglycerols and nonesterified fatty acids, and up-regulated the expression of both lipolytic and lipogenic genes as determined by real-time RT-PCR. Furthermore, CORT impaired mitochondrial biogenesis and oxidative function in epididymal WAT. The reactive oxygen species production was increased and the activities of anti-oxidative enzymes were reduced by CORT treatment as well. Taken together, these findings reveal that chronic CORT administration-induced epididymal adiposity is, at least in part, associated with mitochondrial dysfunction in mouse epididymal white adipose tissue.     

Retroperitoneal white adipose tissue lipoprotein lipase activity is rapidly down-regulated in response to acute stress

Tissue-specific regulation of LPL has been widely studied in rats. Previous studies reported that in vivo administration of adrenaline and acute stress cause an increase in plasma LPL activity coinciding with a decrease in white adipose tissue (WAT) LPL activity. We studied the speed of LPL activity changes during 30 min of stress by immobilization (IMMO) in rats. A first experimental approach in permanently cannulated rats permitted sequential blood sampling in the same animal during IMMO and the obtaining of hemodynamic parameters. In a second experimental approach, animals were euthanized at different times after the start of IMMO to determine LPL activity in tissues. Stress was characterized by rises in blood pressure, heart rate, plasma corticosterone, and available circulating energy substrates. Five min after the start of IMMO, LPL activity fell in retroperitoneal WAT and increased in plasma. These data show the quickest LPL activity change ever described in response to a physiological situation. The speed and simultaneity of these changes suggest that the release from endothelium to the bloodstream may constitute a fast nonexplored mechanism of tissue LPL activity regulation, involved in the lipid energy-substrate redistribution between tissues needed to prepare the "fight-or-flight" response.     

Lipoprotein lipase in adipose tissues of rats running during cold exposure

This study evaluated the individual and combined effects of exercise training and intermittent cold exposure of similar energy cost on serum lipids and lipoprotein lipase (LPL) activity on epididymal white (WAT) and interscapular brown (BAT) adipose tissues of the rat. The animals were subjected daily to 2 h of treadmill running at 24 degrees C or for the same period of time at -5 degrees C, with or without exercise, for 28 days. Exercise training lowered serum triglycerides (P less than 0.01), whereas serum cholesterol was reduced by cold exposure (P less than 0.05). Cholesterol lowering occurred in the lipoproteins of lower densities. WAT weight was diminished by both treatments. Exercise training had an overall lowering effect on WAT total LPL activity (P less than 0.05), whereas cold exposure did not affect enzyme activity significantly. Exercise and intermittent cold interacted on BAT weight. Cold increased total BAT LPL activity (P less than 0.03), whereas simultaneous exercise in the cold greatly diminished this effect. Serum insulin levels were not affected by either treatment. Thus, in WAT, intermittent exposure to cold did not have any lasting effect on LPL activity, whereas exercise training decreased the latter. In contrast, exercise did not influence LPL in BAT of rats not exposed to cold but prevented the stimulation of enzyme activity induced by repeated cold exposure. These results support the notion that the regulation of LPL is tissue specific.     

Divergent effects of leptin in mice susceptible or resistant to obesity.

Consumption of a high-fat diet decreases hypothalamic neuropeptide Y (NPY) and increases proopiomelanocortin (POMC) and brown adipose uncoupling protein (UCP)-1 mRNA in obesity-resistant SWR/J but not obesity-prone C57Bl/6J mice. Although leptin was elevated in both strains in response to a high-fat diet, its role in the development of diet-induced obesity has remained unclear since insulin and other factors that affect similar tissue targets are altered. Thus, we administered recombinant leptin by subcutaneous infusion to chow-fed mice to mimic the changes in plasma leptin across its broad physiologic range. We observed strain differences in responsiveness to reduced and elevated leptin levels. A reduction in leptin during fasting evoked a greater response in C57Bl/6J mice by decreasing energy expenditure and thyroxin, increasing corticosterone and stimulating food intake and weight gain during refeeding. However, C57Bl/6J mice were less responsive to an increase in leptin in the fed state. Conversely, the leptin-mediated response to fasting was blunted in SWR/J mice, whereas an increase in leptin profoundly reduced food intake and body weight in SWR/J mice fed ad libitum. Sensitivity to fasting in C57Bl/6J mice was associated with higher hypothalamic NPY mRNA and reduced POMC and UCP-1 mRNA expression, while the robust response to high leptin levels in SWR/J mice was associated with suppression of NPY mRNA. These results indicate that differences in leptin responsiveness between strains might occur centrally or peripherally, leading to alteration in the patterns of food intake, thermogenesis and energy storage.