β1 Adrenergic receptor is key to cold- and diet-induced thermogenesis in mice (original) (raw)
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1 Adrenergic receptor is key to cold- and diet-induced thermogenesis in mice
Journal of Endocrinology, 2012
Brown adipose tissue (BAT) is predominantly regulated by the sympathetic nervous system (SNS) and the adrenergic receptor signaling pathway. Knowing that a mouse with triple b-receptor knockout (KO) is cold intolerant and obese, we evaluated the independent role played by the b 1 isoform in energy homeostasis. First, the 30 min i.v. infusion of norepinephrine (NE) or the b 1 selective agonist dobutamine (DB) resulted in similar interscapular BAT (iBAT) thermal response in WT mice. Secondly, mice with targeted disruption of the b 1 gene (KO of b 1 adrenergic receptor (b 1 KO)) developed hypothermia during cold exposure and exhibited decreased iBAT thermal response to NE or DB infusion. Thirdly, when placed on a high-fat diet (HFD; 40% fat) for 5 weeks, b 1 KO mice were more susceptible to obesity than WT controls and failed to develop diet-induced thermogenesis as assessed by BAT Ucp1 mRNA levels and oxygen consumption. Furthermore, b 1 KO mice exhibited fasting hyperglycemia and more intense glucose intolerance, hypercholesterolemia, and hypertriglyceridemia when placed on the HFD, developing marked non-alcoholic steatohepatitis. In conclusion, the b 1 signaling pathway mediates most of the SNS stimulation of adaptive thermogenesis. exposure (4 8C) for 3 h of C57 (WT) and b 1 KO; *P!0 . 05 and **P!0 . 001 vs WT; (B) oxygen consumption during decreasing temperature exposure of C57 (WT) and b1KO mice; *P!0 . 001 vs WT; (C) BAT thermogenic response to NE infusion of C57 (WT) and b1KO mice; *P!0 . 004 vs WT; (D) BAT thermogenic response during infusion of DB of C57 (WT) and b1KO mice; *P!0 . 004 vs WT; entries are meanGS.E.M. of six animals per group. b 1 in adaptive thermogenesis . C B UETA, G W FERNANDES and others 361 www.endocrinology-journals.org Journal of Endocrinology (2012) 214, 359-365 a P!0 . 001 vs WT. b P!0 . 01 vs b 1 KO. c P!0 . 001 vs WT HF.
American Journal of Physiology-Endocrinology and Metabolism, 2011
With the finding that brown adipose tissue is present and negatively correlated to obesity in adult man, finding the mechanism(s) of how to activate brown adipose tissue in humans could be important in combating obesity, type 2 diabetes, and their complications. In mice, the main regulator of nonshivering thermogenesis in brown adipose tissue is norepinephrine acting predominantly via β3-adrenergic receptors. However, vast majorities of β3-adrenergic agonists have so far not been able to stimulate human β3-adrenergic receptors or brown adipose tissue activity, and it was postulated that human brown adipose tissue could be regulated instead by β1-adrenergic receptors. Therefore, we have investigated the signaling pathways, specifically pathways to nonshivering thermogenesis, in mice lacking β3-adrenergic receptors. Wild-type and β3-knockout mice were either exposed to acute cold (up to 12 h) or acclimated for 7 wk to cold, and parameters related to metabolism and brown adipose tissue...
Inactivation of the adrenergic receptor β2 disrupts glucose homeostasis in mice
The Journal of endocrinology, 2014
Three types of beta adrenergic receptors (ARβ1-3) mediate the sympathetic activation of brown adipose tissue (BAT), the key thermogenic site for mice which is also present in adult humans. In this study, we evaluated adaptive thermogenesis and metabolic profile of a mouse with Arβ2 knockout (ARβ2KO). At room temperature, ARβ2KO mice have normal core temperature and, upon acute cold exposure (4 °C for 4 h), ARβ2KO mice accelerate energy expenditure normally and attempt to maintain body temperature. ARβ2KO mice also exhibited normal interscapular BAT thermal profiles during a 30-min infusion of norepinephrine or dobutamine, possibly due to marked elevation of interscapular BAT (iBAT) and of Arβ1, and Arβ3 mRNA levels. In addition, ARβ2KO mice exhibit similar body weight, adiposity, fasting plasma glucose, cholesterol, and triglycerides when compared with WT controls, but exhibit marked fasting hyperinsulinemia and elevation in hepatic Pepck (Pck1) mRNA levels. The animals were fed a h...
FEBS Letters, 2002
Catecholamines are viewed as major stimulants of diet-and cold-induced thermogenesis and of fasting-induced lipolysis, through the L L-adrenoceptors (L L 1 /L L 2 /L L 3 ). To test this hypothesis, we generated L L 1 /L L 2 /L L 3 -adrenoceptor triple knockout (TKO) mice and compared them to wild type animals. TKO mice exhibited normophagic obesity and cold-intolerance. Their brown fat had impaired morphology and lacked responses to cold of uncoupling protein-1 expression. In contrast, TKO mice had higher circulating levels of free fatty acids and glycerol at basal and fasted states, suggesting enhanced lipolysis. Hence, L L-adrenergic signalling is essential for the resistance to obesity and cold, but not for the lipolytic response to fasting.
2019
Background and aim: Rodents are commonly housed below thermoneutrality and this exposure to cold (i.e. 20°C) activates thermogenic brown (BAT) and beiging of white adipose tissue. Here, we examined whether a standard housing temperature (i.e. 20°C, a reduction in temperature of ~8°C) or YM-178, a highly-selective β-adrenoreceptor agonist, in obese animals raised at thermoneutrality, would impact differently on classical BAT or subcutaneous inguinal (IWAT) beige depots. Methods: Eighteen weanling Sprague-Dawley rats were housed at thermoneutrality (28°C) and fed a high-fat diet. At 12 weeks, 6 animals were randomised to either standard housing temperature (20°C, n=6) or to β3-AR agonist administration (28°C+β, 0.75mg/kg/d, n=6) for 4 weeks. Metabolic assessment was undertaken during the final 48h, followed by interscapular, perivascular BAT and IWAT sampling for the analysis of thermogenic genes and the proteome. Results: Exposure to 20°C increased weight gain, BAT and IWAT mass. Pro...
The -Adrenergic Receptors and the Control of Adipose Tissue Metabolism and Thermogenesis
Recent Progress in Hormone Research, 2001
The g-adrenergic receptors (OARS) are members of the large family of G protein-coupled receptors. There are three PAR subtypes &AR, g2AR &AR), each of which is coupled to Gas and the stimulation of intracellular CAMP levels. While g,AR and gzAR are broadly expressed throughout tissues of the body, &AR is found predominantly in adipocytes. Stimulation of the PARS leads to lipolysis in white adipocytes and nonshivering thermogenesis in brown fat. However, in essentially all animal models of obesity, the PAR system is dysfunctional and the ability to stimulate lipolysis and thermogenesis is impaired. Nevertheless, we and others have shown that selective g,AR agonists are able to prevent or reverse obesity and the loss ofpAR expression and to stimulate thermogenesis. This chapter will review the current understanding of the role of the sympathetic nervous system and the adipocyte PARS in models of obesity; the physiologic impact of changes in BAR expression on body composition and thermogenesis; and the regulation and unique properties of PAR subtypes in brown and white adipocytes. The latter includes our recent discovery of novel signal transduction mechanisms utilized by &AR to activate simultaneously the protein kinase A and MAP kinase pathways. The impact of understanding these pathways and their potential role in modulating adaptive thermogenesis is discussed. I. Thermogenesis: Control of Heat Generation and Body Composition A. BROWN FAT THERMOGENESIS AND UNCOUPLING OF MITOCHONDRIAL RESPIRATION The rich and varied history of brown adipose tissue (BAT) as an anatomically discrete tissue type included speculations during the 17th century that it was part of the thymus and, a century later, that it was an endocrine organ involved in blood formation or a form of fat acting as a reservoir for certain nutrients (Lindberg, 1970). It wasn't until 1961 that BAT was proposed to be thermogenic (Ball and Jungas, 1961; Smith, 1961). Since that time, an immense body of work has shown that BAT is uniquely capable of responding to various environmental stimuli to generate heat from stored metabolic energy. In response to sympathetic 309
Sympathetic control of glucagon receptor mRNA levels in brown adipose tissue of cold-exposed rats
Molecular and Cellular Biochemistry, 2000
Brown adipose tissue (BAT) is implicated in both cold-induced thermogenesis and regulation of energy expenditure and is mainly controlled by sympathetic innervation. To clarify the permissive and/or complementary roles of glucagon in cold-induced BAT activation, glucagon receptor gene expression and its modulation by sympathetic activity were investigated in rats. One pad of interscapular BAT was surgically denervated while the other pad was sham operated, then rats were either cold-exposed (CE) for 1 week at 4°C or kept near thermoneutrality (25°C, TN). Using a semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay, it was shown that cold exposure decreased (-44%) the relative abundance of BAT glucagon receptor mRNA, an effect which was prevented by unilateral surgical sympathectomy of BAT. The present results show a negative control by sympathetic nervous activity of glucagon receptor gene expression and/or of glucagon receptor mRNA stability in BAT of cold-exposed rats. The down-regulation of glucagon receptor expression during cold exposure does not support a major role of the peptide in the thermogenic control of BAT.
Pfl�gers Archiv - European Journal of Physiology, 2005
During cold exposure, homeothermic animals mobilize glucose with higher efficiency than at thermoneutrality. An interaction between the insulin signal transduction machinery and high sympathetic tonus is thought to play an important role in this phenomenon. In the present study, rats were exposed to cold during 8 days and treated, or not, with a b3-adrenergic agonist, BRL37344 sodium 4-2-2-(3-chlorophenyl)-2-hydroxyethyl amino propyl phenoxy-acetic acid sodium (BRL37344), or antagonist, SR59230A 3-(2-ethylphenoxy)-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2propanol oxalate (SR59230A), to evaluate the cross-talk between insulin and b3-adrenergic intracellular signaling in brown adipose tissue. The drugs did not modify food ingestion, body temperature, and body weight in control and cold-exposed rats. Treatment of control rats with BRL37344 led to higher insulin-induced tyrosine phosphorylation of the insulin receptors, insulin receptor substrate (IRS)-1 and ERK, higher insulin-induced IRS-1/PI3-kinase association, and higher [Ser 473 ] phosphorylation of Akt. Cold exposure alone promoted higher insulin-induced tyrosine phosphorylation of the insulin receptors, IRS-1, IRS-2, and ERK, and higher insulininduced IRS-1 and IRS-2/PI3-kinase association. Except for the regulation of ERK, SR59230A abolished all the cold-induced effects upon the insulin signal transduction pathway. However, this antagonist only partially inhibited the cold-induced increase of glucose uptake. Thus, the sympathetic tonus generated during coldexposure acts, in brown adipose tissue, through the b3-adrenergic receptor and modulates insulin signal transduction, with the exception of ERK. However, insulin-independent mechanisms other than b3-adrenergic activation participate in cold-induced glucose uptake in brown adipose tissue of rats.
β-Adrenergic Receptors, Diet-induced Thermogenesis, and Obesity
Journal of Biological Chemistry, 2003
There is increased awareness that energy expenditure is an important component of weight control and that its dysregulation promotes obesity. This minireview will examine the role of energy expenditure in regulating fat stores, the underlying mitochondrial basis for energy expenditure, and implications of this for potential mechanisms of adaptive thermogenesis and then discuss, in detail, recent evidence regarding the important role of -adrenergic receptors in diet-induced thermogenesis and prevention of diet-induced obesity. Energy Balance Fat is stored when the number of calories consumed exceeds the number of calories expended. In principle, obesity could be caused by increased food intake or decreased energy expenditure or from a combination of the two. Indeed, most single gene mutation models of rodent obesity, whether naturally occurring or genetically engineered, have both increased food intake and decreased energy expenditure. The frequent occurrence of combined abnormalities strongly supports the view that systems exist to match energy expenditure to food intake over time and that dysfunction of both arms is required to produce massive obesity. The power and precision of this system is demonstrated by the fact that most individuals are not obese, despite the thermodynamic reality that a slight mismatch between intake and expenditure is all that is necessary to produce marked weight gain. Although components of this energy balance system have been identified, including leptin, the leptin receptor, ␣-melanocyte-stimulating hormone, the melanocortin-4 receptor, and now ARs 1 (1-6), many questions still remain. For example, what is the wiring diagram of central neural circuits regulating energy balance? Also, and relevant to this review, what are the efferent pathways, i.e. nerves and hormones, target tissues, and intracellular mechanisms, by which the brain controls energy expenditure? Evidence That Energy Expenditure Is Defective in Obesity The strongest support for defects in energy expenditure in obesity comes from monogenic rodent models such as ob/ob, db/db, and melanocortin-4 receptor gene knockout mice. When food intake of these mutant animals, deficient in either leptin, leptin receptors, or melanocortin-4 receptors, is restricted to that of wild-type controls, a maneuver termed pair feeding, marked obesity still develops (7). Animals with experimentally induced hypothalamic lesions also become obese when pair fed to sham-treated controls (8). In fact, there are few exceptions to the rule that animal models of obesity, whether genetic or lesion-induced, have decreased energy expenditure. The situation in humans is less clear. In large part, this is because of difficulties in studying heterogeneous populations, the * This minireview will be reprinted in the 2003 Minireview Compendium, which will be available in January, 2004. This is the second article of six in the "New Animal Models for Study of Metabolism'' Minireview Series.