Reduced norepinephrine turnover in brown adipose tissue of ob/ob mice

Obese (ob/ob) mice have a lower thermogenic capacity than lean mice. The possible role of brown adipose tissue (BAT) in this defect was investigated. Lean and obese mice were exposed to 33 (thermoneutral), 25, or 14 degrees C for up to 3 wk. BAT cytochrome oxidase activity and numbers of Na+-K+-ATPase enzyme units, enzymes involved in thermogenesis, were similar at 33 or 25 degrees C. Chronic exposure to 14 degrees C increased these enzymes 34 and 62%, respectively, in lean mice and nearly 150% in obese mice. Sympathetic nervous system activity, which stimulates thermogenesis in BAT, was evaluated by measuring norepinephrine (NE) turnover. At 25 degrees C, NE turnover rate in BAT of obese mice was only 40% as rapid as in BAT of lean mice. Chronic exposure to 33 degrees C depressed NE turnover in BAT of lean mice, but not in obese mice, whereas exposure to 14 degrees C accelerated NE turnover in both lean and obese mice. Lower sympathetic nervous system activity in BAT of obese mice at 25 degrees C is likely a major factor in their reduced nonshivering thermogenesis and resultant high efficiency of energy storage.     

Effects of cold acclimation on cold-induced changes in lipid metabolism of rat brown adipose tissue.

Effects of acute cold exposure (0 degree C, 12 h) on lipid metabolism of the interscapular brown adipose tissue (BAT) were studied in warm controls (25 degrees C) (WC) and cold-acclimated rats (5 degrees C, 4 weeks) (CA). 1) We confirmed that cold acclimation brought about decreased BAT triglyceride (TG) level and increased BAT phospholipid (PL) level. The indexes of unsaturation, such as unsaturation index and polyunsaturated fatty acids/saturated fatty acids ratio, of bulky fatty acids (FA) (palmitic, stearic, oleic, and linoleic acids) decreased in TG, while those increased in PL. Rare FA (eicosadienoic acid, homo-gamma-linoleinic acid, lignoceric acid) level, which were about five times higher in PL than TG in WC, decreased in both TG and PL in CA. 2) Effect of acute cold exposure in WC: The level as well as the amount of TG in BAT was greatly reduced and the indexes of unsaturation in TG-FA increased. The most part of reduced TG (85%) was explained by the bulky FA. Rare FA explained only 1.1% of reduced TG. PL level in BAT did not change, but its amount decreased. The indexes of unsaturation increased in PL-FA. 3) Effect of acute cold exposure in CA: CA was placed in warm temperature of 25 degrees C before cold exposure. In contrast with the cold-reduced TG in WC, either the level or the total amount of TG in BAT did not change, but the indexes of unsaturation in TG-FA decreased. The level as well as the total amount of PL in BAT increased. The arachidonic index and arachidonate in PL-FA decreased, but the indexes of unsaturation did not change. These results indicate as a whole that acute cold exposure as well as cold acclimation influences BAT lipid metabolism in FA compositions as well as amount of TG and PL, suggesting that such changes are related to thermogenic activity of this tissue.     

Ultrastructural effects of chemical sympathectomy on brown adipose tissue

Summary Adult rats maintained at 20–22 °C, were exposed to 4 °C for 30–60 min and injected with 50 or 100 mg/kg 6-hydroxydopamine (6-OHDA) in an attempt to achieve a similar degree of chemical sympathectomy of nerves terminating among the adipocytes and the smooth muscle cells of the blood vessels in the interscapular brown adipose tissue (BAT). After 1, 4 or 10 days the pads of BAT were removed and small sections from each pad prepared for electron microscopy; the remaining tissue was used for noradrenaline (NA) analysis or fluorescence histochemistry.Ultrastructural observations showed that 24 h after the 6-OHDA injection virtually all noradrenergic nerve terminals were distorted and contained aggregates of degenerated cell organelles. The destruction could be correlated with a disappearance of fluorescent varicosities and a reduction of measurable NA to 8–12% of the control value. There was no differential toxic effect of 6-OHDA on the terminals among the adipocytes compared to those associated with blood vessels. Thus, treatment with 6-OHDA is more effective than previous attempts using immunological or surgical methods to produce sympathectomy, because both of the latter methods only eliminate the innervation of the blood vessels and spare the nerve terminals of the adipocytes.4 days after 6-OHDA injection there was no improvement in the morphology of the terminals but after 10 days there was an increase in the number of terminals and axons with a normal appearance and this was paralleled by an increase in extractable NA to 50% of the control value.Because of the relatively rapid recovery of NA content and reappearance of terminals of normal appearance within 10 days after 6-OHDA injection, these animals should be injected weekly when a more permanent sympathectomy of adipocytes and blood vessels is desired.     

Prenatal and lactation nicotine exposure affects morphology and function of brown adipose tissue in male rat offspring

The aim of this study was to investigate the effects of prenatal and lactation nicotine exposure on the morphology and function of brown adipose tissue (BAT) in male rat offspring. We conducted a morphological assay and gene expression study of interscapular BAT (iBAT) in male rat offspring. The male offspring from nicotine-exposed dams exhibited higher body weight and iBAT weight. Hematoxylin and eosin staining and transmission electron microscopy showed that iBAT from nicotine-exposed male offspring presented a “whitening” phenotype characterized by lipid droplet accumulation and impaired mitochondria with a randomly oriented and fractured cristae. The expression of the iBAT structure and function-related genes all decreased in nicotine-exposed male offspring. These data indicate that prenatal and lactation nicotine exposure affects morphology and function of iBAT in male rat offspring.     

A new, powerful player in lipoprotein metabolism: brown adipose tissue

Important causes for modern epidemics such as obesity, diabetes, and cardiovascular disease are over- and malnutrition. Dietary as well as endogenous lipids are transported through the bloodstream in lipoproteins, and disturbances in lipoprotein metabolism are associated with atherosclerosis, heart disease, and diabetes. Recent findings reveal biological principles-how lipoproteins, in particular triglyceride-rich lipoproteins, are metabolized and what factors regulate their processing. The fate of triglycerides delivered by lipoproteins is quite simple: either they can be stored or they can be utilized for combustion or biosynthetic pathways. In the healthy state, fatty acids derived from triglycerides can be burned in the heart, muscle, and other organs for actual work load, or they can be stored in white adipose tissue. The combination of storage and combustion is realized in brown adipose tissue (BAT), a peripheral organ that was long thought to be only of relevance in small mammals: Recent data however prove that BAT plays an important role in human adults. Here, we will review recent insights on how BAT controls triglyceride clearance and the possible implications for the treatment of chronic diseases caused by lipid mishandling.     

Metabolic effects of nicotine on human adipose tissue in organ culture

Summary Fragments of human adipose tissue were maintained in culture for 1 week in a medium containing 1 mU/ml insulin and 100 ng/ml dexamethasone. Under these conditions lipoprotein lipase activity was present in human adipose tissue fragments which converted [¹⁴C]glucose to ¹⁴C0₂ and [¹⁴C]triglyceride. Both metabolic parameters studied were affected by human tumor necrosis factor and brefeldin A. When fragments of human adipose tissue after 1 week in culture were incubated with nicotine tartrate for 20 h, a slight but significant increase in lipoprotein lipase activity was observed, and an increased conversion of [¹⁴C]glucose to ¹⁴CO₂ and [¹⁴C] triglyceride occurred. Nicotin was taken up by human adipose tissue, but no conversion to cotinine was observed. Our data demonstrate a direct effect of nicotine on human adipose tissue metabolism. Furthermore, it is suggested that weight loss in smokers is a multifactorial phenomenon, and one of the important factors to be considered is the direct effect of nicotine within the tissue.Abbreviations LPL lipoprotein lipase - MEM minimal essential medium - rHuTNF recombinant human tumor necrosis factor - BFA brefeldin A - TG triglyceride     

Suppression of brown adipose tissue metabolism following intraventricular bombesin in rats

The effects of intraventricular bombesin (BS) at doses of 0.1, 1.0, and 10.0 micrograms on thermoregulatory and cardiovascular functions were studied in conscious rats with a direct calorimeter at ambient temperatures (Ta) of 18, 23, and 28 degrees C. At two lower TaS, the central BS produced a profound decrease in colonic temperature (Tcol) with a reduction of the temperature difference between the interscapular brown adipose tissue (BAT) and the colon (TBAT-Tcol). Increases in nonevaporative and evaporative heat losses and mean arterial blood pressure (BP) were consistent following the central BS at any dose tested at any Ta. In the sinoaortic deafferentated rats, a 0.1 microgram of BS produced hypothermia with a significant decrease in (TBAT-Tcol) and heat production (M). Changes in Tcol, (TBAT-Tcol), and M in the denervated rats, however, were not different from those in the sham-operated rats. These results suggest that the central BS suppresses BAT thermogenesis and facilitates heat loss mechanisms. The baroreflex-mediated metabolic reduction is not the case in the BS-induced hypothermia in rats.     

Gangliosides and energy substrates in brown adipose tissue of cold-acclimated rat

Effect of cold acclimation on gangliosides as well as triglyceride and glycogen in brown adipose tissue was studied in rats. Ganglioside GM3 level per unit fresh weight and per unit fat-free-dry-matter was significantly higher in cold-acclimated rats (CA) than in warm controls, while the tissue triglyceride and glycogen levels were lower in CA. GM3 may be involved in cold-induced proliferation and differentiation of brown adipose tissue.     

Sexual dimorphism in the adrenergic control of rat brown adipose tissue response to overfeeding

Gender-related differences in the brown adipose tissue (BAT) response to overfeeding rats on a cafeteria diet were studied by assessing the balance between the expression of beta-adrenoceptors (beta1-, beta2-, beta3-AR) and alpha2A-AR and their relation to the expression of uncoupling proteins (UCP1, UCP2, UCP3). Cafeteria diet feeding for 15 days, which involved a similar degree of hyperphagia in both sexes, led to a greater body weight excess in females than in males and a lower activation of thermogenesis. Gender-related differences were found for different adrenoceptor expression and protein levels, which might explain, in part, sex differences in the thermogenic parameters. The lower expression of alpha2A-AR in females than in males could be responsible for the higher expression of UCP1 and thermogenic capacity under non-hyperphagic conditions. However, in a situation of high adrenergic stimulation--as occurs with overfeeding--as there is a preferential recruitment of the beta3-AR by noradrenaline compared with other adrenergic receptors, the higher levels of beta3-AR in males rats than in females could be responsible for the greater thermogenic capacity and the lesser weight gain in males. Thus, the alpha2/beta3 balance in BAT could be a key in the thermogenic control.     

Differential responses of white adipose tissue and brown adipose tissue to caloric restriction in rats

Caloric restriction (CR) slows the aging process and extends longevity, but the exact underlying mechanisms remain debatable. It has recently been suggested that the beneficial action of CR may be mediated in part by adipose tissue remodeling. Mammals have two types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT). In this study, proteome analysis using two-dimensional gel electrophoresis combined with MALDI-TOF MS, and subsequent analyses were performed on both WAT and BAT from 9-month-old male rats fed ad libitum or subjected to CR for 6 months. Our findings suggest that CR activates mitochondrial energy metabolism and fatty acid biosynthesis in WAT. It is likely that in CR animals WAT functions as an energy transducer from glucose to energy-dense lipid. In contrast, in BAT CR either had no effect on, or down-regulated, the mitochondrial electron transport chain, but enhanced fatty acid biosynthesis. This suggests that in CR animals BAT may change its function from an energy consuming system to an energy reservoir system. Based on our findings, we conclude that WAT and BAT cooperate to use energy effectively via a differential response of mitochondrial function to CR.     

Effects of portacaval diversion on lipid metabolism in rat adipose tissue

Male rats were submitted for 3 wk either to portacaval shunt or to portacaval transposition. In both cases, sham-operated pair-fed rats served as controls. After an overnight fast, insulinemia was similar in all groups, but glucagonemia was significantly higher (by 65%) and serum glucose significantly lower (by 35%) in rats with a portacaval shunt. The lipid metabolism of epididymal adipose tissue was studied in vitro, as well as in vivo. In rats with a portacaval shunt, in vitro lipogenesis from [U-14C]glucose, [1-14C]acetate, or 3H2o was 60-80% lower than in sham-operated pair-fed controls. Twice as much in vitro basal lipolysis could be determined. In addition, in vivo lipogenesis from 3H2O was markedly decreased (6 times). By contrast, in rats with portacaval transposition, in vitro lipogenesis was higher (by 80-140%) and basal lipolysis lower (by 63%) than in pair-fed controls. Thus, even when the nutritional state was taken into consideration, the type of portal diversion was the determining factor in influencing lipid metabolism in epididymal adipose tissue.     

Activation of brown adipose tissue thermogenesis increases slow wave sleep in rat

Considering the thermoregulatory role of slow wave sleep (SWS), we wondered whether the sole increase of brown adipose tissue (BAT) thermogenesis could enhance this sleep state. We tested this hypothesis by administering to rats an agonist (BRL 37,344) of the beta-3 adrenoceptor subtype that is massively localized in BAT cell membrane and that is known to activate BAT thermogenesis. Sleep was electrographically characterized. The temperature of interscapular BAT (Tibat) and cortex (Tco) were also assessed. Tibat significantly increased 2-3 h after BRL injection (but not Tco), concomitantly with SWS (+56-57%). At the maximum of Tibat, a significant positive correlation was found between their changes and those of SWS. We demonstrated for the first time that sleep (and especially SWS) can be affected by the specific activation of BAT.