Impaired metabolic response to nerve stimulation in brown adipose tissue of hypothyroid rats

In brown adipose tissue of the rat, chemically or surgically induced hypothyroidism caused the following effects. A large decrease of the magnitude of the metabolic response to electrical nerve stimulation. The deactivation half-time of the response was reduced to 70% of the control value, with no change in catechol O-methyltransferase activity. Pre-incubation of tissues with norepinephrine, 10(-5) M, increased the response to subsequent nerve stimulation almost to that of the controls. The catecholamine analogue dose-response curves were shifted to the right. The shift was very pronounced for isoproterenol (K50 426 nM versus 2 nM), somewhat less marked for norepinephrine (7373 nM versus 194) and very slight for phenylephrine (2803 nM versus 1649); there was almost no change in Emax values. An increase of octanoate oxidative capacity. A decrease of the capacity of the stereoselective binding of (-)-[3H]dihydroalprenolol of the high-affinity (Kd 2.0 nM) sites to a fourth of the control value and an increase by a factor of 2.9 of the Kd of the low-affinity binding sites. This decrease of binding to the beta-receptors was not sufficient quantitatively to explain the decrease in the metabolic response, suggesting the existence of an additional defective reaction which could occur between the binding to the beta-receptors and the activation of the triglyceride lipase. These results show that the sharp decrease of the metabolic response of brown adipose tissue to nerve stimulation has multiple causes. The findings are discussed in the context of the drastic decrease of cold resistance in hypothyroid rats.     

Reduced norepinephrine turnover in interscapular brown adipose tissue of obese rats after ovariectomy

Norepinephrine (NE) turnover, which is a reliable indicator of sympathetic nervous system (SNS) activity, was measured in the interscapular brown adipose tissue (IBAT), heart, and pancreas of ovariectomized (OVX), sham-operated rats receiving injections of estradiol benzoate (EB). Ovariectomized rats (OVX rats) ate much more than controls and became obese, whereas the administration of EB to obese OVX rats decreased their food intake to the level below that of sham-operated animals and body weight to the level of sham controls. The results from studies using the inhibition of NE biosynthesis with alpha-methyl-p-tyrosine or radiolabeled NE to measure NE turnover significantly demonstrated reductions in SNS activity in IBAT of OVX rats than in sham controls, whereas the injections of EB to OVX rats significantly restored the decrease of NE turnover in IBAT. NE turnover in heart and pancreas were similar in these three groups. It is suggested that reduced NE turnover in IBAT may be a major factor in the development of obesity after ovariectomy (OVX).     

Molecular approach to thermogenesis in brown adipose tissue: cDNA cloning of the mitochondrial uncoupling protein.

The uncoupling protein (UCP) of mammalian brown fat is a specialized and unique component responsible for energy dissipation as heat. Translation and immunoprecipitation from sucrose-fractionated mRNA indicated that the mRNA of UCP sedimented at 14-16 S. A recombinant cDNA library prepared from mRNA of thermoactive brown fat enriched for UCP mRNA has been constructed and cloned in Escherichia coli. Recombinant plasmids were screened by differential colony hybridization to a cDNA probe complementary to poly(A)+ RNA isolated from thermogenic or from weakly thermogenic brown fat. Several differentially hybridizing plasmids were shown to contain UCP cDNA sequences by their ability to select a mRNA coding for an in vitro translation product that was immunoprecipitable with antibodies against UCP. Blot hybridization of brown fat mRNA to a 32P-labeled UCP cDNA probe revealed two major species of mRNA (15S and 18S). As compared to non-thermogenic tissue, a strikingly increased hybridization to the probe was observed with brown fat mRNA from thermoactive tissue. Moreover, hybridization was observed with RNA of brown adipose tissue from rat, hamster, or mouse but not with RNA from rat or mouse liver.     

Lipoprotein lipase activity and cellularity in brown and white adipose tissue in Zucker obese rats

The genetically obese adult Zucker rat (fafa) exhibits reduced thermogenesis when stimulated by physiological agents (cold, catecholamines). Recent evidence suggests that this thermogenic defect may be important in the manifestation of the animal's obesity and that it reflects a reduced thermogenic contribution from brown adipose tissue, the major nonshivering thermogenic site in many mammals. The present study describes the effects of the obese genotype on brown (and white) adipocyte size, number, and lipid content and tissue lipoprotein lipase (LPL) activity. In the obese rats, brown fat depots were increased in mass. This increase could be accounted for by brown fat hypertrophy (due primarily to an increase in the amount of triglyceride present in each cell) rather than hyperplasia (there being no increase in the number of brown fat cells). In addition, unlike the situation in white fat, the brown fat from the obese rats did not exhibit higher LPL activity than did the brown fat from their lean littermates. This absence of an increased capacity for triglyceride uptake, coupled with the greater amount of triglyceride per brown adipocyte, is consistent with a reduction of triglyceride oxidation (and, thus, heat production) in the cells from the obese (v the lean) rats.     

The effects of 2-deoxy-D-glucose on brown adipose tissue of lean and obese Zucker rats

The response of brown adipose tissue (BAT) thermogenesis, as measured by mitochondrial GDP binding, of lean and obese Zucker fa/fa rats to 2-deoxy-D-glucose (2-DOG) has been investigated. 2-DOG reduced BAT mitochondrial GDP binding of lean rats but had no effect in obese rats. Adrenalectomy increased BAT GDP binding in obese rats and restored the 2-DOG inhibitory effect. Corticosterone inhibited GDP binding in lean rats and abolished the 2-DOG inhibitory effect. 2-DOG induced hyperphagia and hyperglycaemia in lean rats, but these effects were either absent or attenuated in the obese. The possibility that a glucocorticoid inhibition of glucose metabolism impairs sympathetic activity in the obese rats is discussed.     

Ephedrine activates brown adipose tissue in lean but not obese humans

Aims/hypothesis

Brown adipose tissue (BAT) activation increases energy consumption and may help in the treatment of obesity. Cold exposure is the main physiological stimulus for BAT thermogenesis and the sympathetic nervous system, which innervates BAT, is essential in this process. However, cold-induced BAT activation is impaired in obese humans. To explore the therapeutic potential of BAT, it is essential to determine whether pharmacological agents can activate BAT.

Methods

We aimed to determine whether BAT can be activated in lean and obese humans after acute administration of an orally bioavailable sympathomimetic. In a randomised, double-blinded, crossover trial, we administered 2.5 mg/kg of oral ephedrine to nine lean (BMI 22?±?1 kg/m²) and nine obese (BMI 36?±?1 kg/m²) young men. On a separate day, a placebo was administered to the same participants. BAT activity was assessed by measuring glucose uptake with [¹⁸F]fluorodeoxyglucose and positron emission tomography–computed tomography imaging.

Results

BAT activity was increased by ephedrine compared with placebo in the lean, but unchanged in the obese, participants. The change in BAT activity after ephedrine compared with placebo was negatively correlated with various indices of body fatness.

Conclusions/interpretation

BAT can be activated via acute, oral administration of the sympathomimetic ephedrine in lean, but not in obese humans.     

Mechanism linking insulin resistance to defective thermogenesis in brown adipose tissue of obese diabetic SHR/N-cp rats.

We previously reported that the decreased sensitivity of brown adipose tissue (BAT) from obese Zucker rats to the calorigenic effects of norepinephrine is associated with a marked resistance to insulin, and we suggested that this defect may explain, at least in part, the increased energy gain efficiency of fa/fa rats. To test whether insulin resistance and/or diabetes leads to a reduced BAT thermogenesis in other genetic models of obesity, we compared BAT metabolic properties of obese Zucker rats with that of obese-nondiabetic LA/N-cp and obese-diabetic SHR/N-cp rats. It was found that the responsiveness and sensitivity of isolated brown adipocytes to the calorigenic effects of norepinephrine (10-100 mM) were markedly reduced in SHR/N-cp rats as compared to their lean controls (the Vmax was decreased by 3-4 times and the EC50 value was doubled). In the same cells, there was a similar decrease in the respiratory effects of dibutyryl cAMP (DBcAMP), revealing the presence of a major post-receptor defect. Remarkably, total cytochrome oxidase activity (an index of cell mitochondrial content) was also decreased by 3-4 times in SHR/N-cp rats, suggesting that a reduced BAT mitochondrial content is responsible for the defective thermogenesis. Similarly to Zucker rats, adipocytes isolated from SHR/N-cp rats were resistant to the metabolic effects of insulin (glucose transport and antithermogenesis). Cells from obese Zucker rats were also desensitized to the metabolic effects of norepinephrine and insulin but their thermogenic capacity was not reduced. In contrast, all the above parameters were normal in obese-nondiabetic LA/N-cp rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Energetic efficiency and brown adipose tissue uncoupling protein of obese Zucker rats fed high-carbohydrate and high-fat diets: the effects of adrenalectomy

The influence of diet on the response of lean and obese fa/fa rats to adrenalectomy has been studied. Adrenalectomized and sham-operated rats were fed either a semi-synthetic high-carbohydrate (HC) or high-fat (HF) diet for 13 days. Energetic efficiency, calculated for measurements of energy storage and energy intake, was increased in obese rats fed both HC and HF diets and reduced close to values of lean rats after adrenalectomy. Brown adipose tissue mitochondrial GDP binding and uncoupling protein concentration were reduced in control obese rats fed both HC and HF diets. After adrenalectomy the level of GDP binding and uncoupling protein concentration were increased to levels of lean rats. Molar ratios of GDP binding to uncoupling protein were similar in lean and obese rats, were unaffected by adrenalectomy, but were elevated in rats fed the HC diet (0.40 +/- 0.02 vs 0.28 +/- 0.03). The data suggests that diet, but not obese genotype, may influence the masking of mitochondrial uncoupling protein.     

Effects of thyroid hormones on mitochondrial oxygen consumption in brown adipose tissue and heart from cold-exposed hypothyroid rats.

The present work measured brown adipose tissue and heart mitochondrial oxygen consumption in hypothyroid rats treated with replacement doses of T3, T4 or T4 plus iopanoic acid and kept at 4 degrees C for 24 h. Heart oxygen consumption in normal, untreated hypothyroid and T4-treated hypothyroid rats was unaffected by cold exposure. In rats treated with T4 plus iopanoic acid, rates of oxygen consumption were normal in those maintained at 4 degrees C as well as in those kept at room temperature, despite serum T3 concentration being significantly decreased. The cold-exposed T3-treated hypothyroid rats showed a marked decrease in oxygen consumption (p less than 0.02) and alpha-glycerophosphate dehydrogenase activity, a T3-dependent enzyme. Mitochondrial oxygen consumption in brown fat from normal (p less than 0.01), T4 (p less than 0.02) and T4 plus iopanoic acid-treated (p less than 0.01) rats rose more than twofold in response to cold. In the T3-treated group, oxygen consumption at room temperature was higher (p less than 0.02) than in any other group at similar temperatures. However, the T3-treated group showed no changes in oxygen consumption in response to cold, perhaps because this group reached the maximal response at room temperature. The untreated and the T3-treated hypothyroid rats (both groups devoid of T4) did not survive at 4 degrees C unless T4 or several-fold replacement amounts of T3 were administered. The data demonstrate the crucial role of T4 in thermogenesis during cold exposure.     

GIRK4在肥胖大鼠脂肪组织中的表达

目的 研究饮食诱导肥胖大鼠G蛋白耦联(门控)内向整流钾离子通道(GIRK4)基因在脂肪组织中的表达,探讨其与肥胖的相关性.方法 30只Sprague-Dawley大鼠随机分为两组:对照组(n=10),予以普通饲料饲喂;肥胖组(n=20),予以高脂肪、高热量饮食饲喂.8周后处死大鼠,提取两组的白色脂肪组织和棕色脂肪组织,...     

Ontogenic loss of brown adipose tissue sensitivity to beta-adrenergic stimulation in the ovine

In ruminants and other large animals, expression of uncoupling protein-1 (UCP1) in brown adipose tissue (BAT) is confined to the perinatal period when it plays a key role in nonshivering thermogenesis. This study determined whether loss of expression of the BAT phenotype was due to reduced response to a beta-agonist, isoprenaline, and expression of the peroxisome proliferator-activated receptor (PPAR) family [PPARalpha, PPARgamma, PPAR coactivator 1alpha (PGC-1alpha)], which regulates UCP1 gene expression. Perirenal adipose tissue (PAT) was sampled from ovine fetuses, newborn lambs, and lambs on d 1, 5, 7, and 21 of life. UCP1 mRNA and protein in PAT increased from d 123 of fetal life to reach a maximum at birth followed by a rapid decrease over the first 5 d of life. Expression of the coactivator, PGC-1alpha and PPAR alpha, peaked between fetal day 123 and birth, and then declined to undetectable levels in the first days of life. In vivo administration of isoprenaline was able to induce expression of UCP1, PGC-1alpha, and PPARalpha in BAT up to 5 d of age but thereafter was ineffective. In vitro addition of beta-receptor, PPARalpha, and PPARgamma agonists were unable to overcome the suppression of UCP1, PPARalpha, and PPARgamma expression observed in differentiated adipocytes prepared from 30-d-old compared with 1-d-old lambs. These data are consistent with a model in which postnatal loss of UCP1 expression and beta-adrenergic induction of the brown adipocyte phenotype is due to loss of expression of PGC-1alpha and PPARalpha.     

Nicotine induces uncoupling protein 1 in white adipose tissue of obese mice.

OBJECTIVE: To test the hypothesis that nicotine not only activates uncoupling protein1 (UCP1) in brown adipose tissue (BAT), but also induces UCP1 in white adipose tissue (WAT), which contributes to the mitigation of obesity in obese mice. DESIGN: Weights of the whole body, the gastrocnemius muscle, interscapular BAT and subcutaneous and retroperitoneal WAT, food intake and the mRNA and protein of UCP1 in these tissues were measured and immunohistochemistry using antiserum against UCP1 was also performed in obese yellow KK mice treated with nicotine for 6 months and control mice treated with physiological saline. RESULTS: Obese mice treated with nicotine for 6 months, compared with those injected with saline, weighed significantly less (P < 0.01) and had smaller subcutaneous and retroperitoneal WAT pads (P < 0.01), while obese mice that received nicotine ate less (P < 0.05) than those injected with saline. In mice treated with nicotine, the mRNA and protein of UCP1 was detected not only in BAT, but also in subcutaneous and retroperitoneal WATs. Immunohistochemically, the BAT of obese mice contained large lipid droplets and appeared rather WAT-like, but changed to typical brown adipocytes after nicotine treatment. The fat pads of nicotine-treated mice contained many multilocular cells that were positive for UCP1. CONCLUSION: Nicotine not only activates UCP1 in BAT, but also induces UCP1 in WAT and decreases food intake, which contributes to the mitigation of obesity.     

Renaissance of brown adipose tissue

The recent discovery of functional brown adipose tissue in human adults raised this tissue again into the focus of current investigations concerning human energy homeostasis. Brown fat is a key thermogenic tissue and is essential for non-shivering thermogenesis in the human newborn and hibernating mammals. This review highlights the biological and molecular aspects of brown adipose tissue development and function from the embryonic state to childhood and adolescence.     

The brown adipose tissue of hyperthyroid rats. A biochemical and ultrastructural study

Male Sprague-Dawley rats were treated with triiodothyronine (100 micrograms/100 g/day) for 2, 4, 7, 14 and 21 days and the biochemical and ultrastructural changes of the brown adipose tissue were investigated. Results showed that the tissue weight, DNA and phospholipid content increased very early (by day 2 or 4) and that triglycerides increased later. These hormonal effects are not inhibited by the beta 1-antagonist propranolol. From the morphological point of view, triiodothyronine administration induced the early proliferation and maturation of adipocyte precursors (interstitial cells and preadipocytes). It is concluded that triiodothyronine administration causes a very early hyperplasia in the brown adipose tissue similar to that observed during exposure to cold by mechanisms that may not be secondary to the involvement of norepinephrine.     

棕色脂肪检测技术的研究进展

目前关于体内棕色脂肪的检测主要分为半定量检测和功能检测两大类.半定量检测方法主要包括正电子发射断层扫描(PET)/CT、MRI等影像学检查,功能检测方法主要包括间接热量测定法、交感神经张力测定法、测温法等.此外,还可以通过称重法、检测棕色脂肪经典标志物表达来评估.对棕色脂肪组织的检测有助于进一步探讨肥胖的发生机制,从而为其治疗提供新的靶点.     

Dietary-induced permanent changes in brown and white adipose tissue composition in rats

We have previously observed that feeding rats a cafeteria diet causes excess weight gain and changes in tissue composition. The object of this study was to assess whether these alterations were sustained after withdrawal of the palatable diet in the rat. The results showed that the obesity was not reversed by feeding a standard diet ad libitum for five months after withdrawal of the cafeteria diet. Body weight was 26 per cent greater than in control rats and tissue composition showed permanent alterations. The excess weight of lumbar white adipose tissue was due mainly to lipid content (86 per cent) and this was also true, but to a less extent, for interscapular brown fat (59 per cent). Increased brown fat mass was a result of hyperplasia and hypertrophy, whereas increased lumbar white fat was mainly a result of hyperplasia alone. In conclusion, changes in tissue composition, particularly in fat depots, were permanent and could be ascribed to the obesity per se, and not to the diet composition.     

Macrophage recruitment in obese adipose tissue

Obesity is characterized as a chronic state of low‐grade inflammation with progressive immune cell infiltration into adipose tissues. Adipose tissue macrophages play critical roles in the establishment of the chronic inflammatory state and metabolic dysfunctions. The novel discovery that pro‐inflammatory macrophages are recruited to obese adipose tissue prompted an increased interest in the interplay between immune cells and metabolism. Since this discovery, many works have been published investigating the factors that lead to macrophage recruitment, the phenotypic change of adipose tissue macrophages, and metabolic dysfunctions. Adipokines and chemokines are key mediators that play crucial roles in crosstalk between adipocytes and macrophages and in regulating the adipose tissue inflammation. In the present review, we discuss the obesity‐mediated adipose tissue remodelling, and particularly, the role of adipokines/chemokines in macrophage recruitment to obese adipose tissue. This review provides new insights into the physiological role of these factors and identifies a potential therapeutic target for obesity and associated disorders.