β 1 /β 2 /β 3 ‐adrenoceptor knockout mice are obese and cold‐sensitive but have normal lipolytic responses to fasting

The current epidemic of childhood obesity will be a serious threat to population health for at least the next several decades. The biology of childhood obesity was the theme of an international symposium held in November 2007. Speakers discussed monogenic causes of obesity, prenatal epigenetic programing, neurobehavioral aspects of obesity, and hormonal and neuroendocrine abnormalities, and the insights provided by non-murine models for understanding the biology of early-onset obesity. Several new developments have been reported in white and brown adipose tissue biology. They are summarized briefly in this review and include observations about cell lineage of adipocytes, the renewal of adipocytes throughout life and the numerous factors that influence adipocyte fatty acid release. The biological underpinnings of childhood obesity are multiple and complex.

Section: Hormone-sensitive Lipasementioning

confidence: 99%

Genetics, physiology and perinatal influences in childhood obesity: view from the Chair

Mitchell

2009

“…The b-less mice exhibited normophagic obesity and a defective cold-induced thermogenesis. 19,20 Furthermore, they did not respond to a high-fat diet by an increase in oxygen consumption, suggesting a failure in their diet-induced thermogenesis. 19 The b-less mouse model would be an invaluable tool to test in vivo the respective contributions of the b-adrenergic system and of putative direct peripheral effects of leptin on thermogenesis and oxidative substrate utilization.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, leptin was infused subcutaneously through osmotic minipumps in wild-type (WT) and b-less mice and its effects on food intake, body weight, energy expenditure, glucose and lipid utilization, as well as BAT thermogenic gene expression were determined. Mice 3-to 4-month-old male WT and b-less mice, obtained as previously described, 20 were housed individually and kept at 24 ± 1 1C on a 12 h light-dark cycle (0700 -1900 hours). They were allowed ad libitum access to water and to a standard laboratory chow (Nordos, Cergy, France) unless otherwise stated.…”

Section: Introductionmentioning

confidence: 99%

Effects of leptin on energy metabolism in β-less mice

Asensio¹,

Arsenijevic²,

Lehr³

et al. 2008

Objective: To investigate the impact of b-adrenoceptor deficiency on the metabolic effects of leptin. Measurements: Leptin was infused subcutaneously through an osmotic minipump in wild-type (WT) and b 1 /b 2 /b 3 -adrenoceptor knockout (b-less) mice and its effects on food intake, energy expenditure, carbohydrate and lipid utilization as well as on the levels of expression of the brown adipose tissue (BAT), thermogenic marker uncoupling protein-1 (UCP1) and type II deiodinase (D2) mRNAs were compared. Results: Leptin treatment decreased food intake by 23% in both the WT and the b-less mice. In pair-fed animals being used as controls, leptin treatment was found to increase energy expenditure in WT, but not in b-less mice. No difference was observed in carbohydrate or fat utilization between leptin-treated WT and b-less mice. Leptin increased UCP1 and D2 mRNA levels in WT mouse BAT 1.7-and 3-fold, respectively, but had no effect on the expression of these genes in b-less mouse BAT. Conclusion: The stimulatory effects of leptin on oxygen consumption, BAT UCP1 and D2 expression require functional b-adrenoceptors, but its inhibitory effect on food intake and its stimulatory effect on fat utilization is independent of the b-adrenoceptor signalling.

“…b-less mice) and mice deficient in UCP1 show impaired thermogenesis and poor tolerance to cold exposure. [5][6][7] However, the findings that only the b-less mice, but not the UCP1-deficient mice, are highly susceptible to develop obesity have also underscored the existence, even in small rodents, of mechanisms other than the SNS-BAT-UCP1 axis in b-adrenergic control of thermogenesis.In the search for insights into these UCP1-independent thermogenic mechanisms under b-adrenergic control, the repression of stearoyl-CoA desaturase 1 (SCD1), a microsomal enzyme that catalyzes the synthesis of monounsaturated fatty acids, is of particular significance. Apart from being components of lipids -that include phospholipids, triglycerides, cholesterol esters, wax esters and alkyldiacylglycerols -these monounsaturated fatty acids also serve as…”

mentioning

confidence: 99%

mentioning

confidence: 99%

β-Adrenergic control of stearoyl-CoA desaturase 1 repression in relation to sympathoadrenal regulation of thermogenesis

Mainieri

Montani

Seydoux³

et al. 2006

Mice lacking b-adrenoceptors, which mediate the thermogenic effects of norepinephrine and epinephrine, show diminished thermogenesis and high susceptibility to obesity, whereas mice lacking stearoyl-CoA desaturase 1 (SCD1), which catalyzes the synthesis of monounsaturated fatty acids, show enhanced thermogenesis and high resistance to obesity. In testing whether b-adrenergic control of thermogenesis might be mediated via repression of the SCD1 gene, we found that in mice lacking b-adrenoceptors, the gene expression of SCD1 is elevated in liver, skeletal muscle and white adipose tissue. In none of these tissues/organs, however, could a link be found between increased sympathetic nervous system activity and diminished SCD1 gene expression when thermogenesis is increased in response to diet or cold, nor is the SCD1 transcript repressed by the administration of epinephrine. Taken together, these studies suggest that the elevated SCD1 transcript in tissues of mice lacking b-adrenoceptors is not a direct effect of blunted b-adrenergic signalling, and that b-adrenergic control of SCD1 repression is unlikely to be a primary effector mechanism in sympathoadrenal regulation of thermogenesis. Whether approaches that target both SCD1 and molecular effectors of thermogenesis under b-adrenergic control might be more effective than targeting SCD1 alone are potential avenues for future research in obesity management. Keywords: thermogenesis; type 2 diabetes; sympathetic nervous system; catecholaminesThe sympathoadrenal system, through the release of norepinephrine from sympathetic nerves innervating peripheral tissues and through circulatory epinephrine released by adrenal medulla, plays an important role in the regulation of mammalian heat production. 1,2 Whereas in large mammals, the sites and molecular mechanisms underlying adrenergic control of heat production are poorly understood, studies in small rodents have implicated an elevation in sympathetic nervous system (SNS) activity in brown adipose tissue (BAT) -via b-adrenoceptor activation of its uncoupling protein (UCP1) -as a common mechanism for the stimulation of thermogenesis in response to both dietary and cold stimuli. 3,4 This contention is supported by the demonstrations that both SNS activity and UCP1 are elevated in BAT from rats and mice exhibiting adaptive increases in thermogenesis in response to cold or to overfeeding, and conversely they are both diminished in BAT from animals showing adaptive suppression of thermogenesis in response to fasting or severe food restriction. A major role for the SNS-BAT-UCP1 axis in thermoregulatory thermogenesis is further supported by the demonstration that mice lacking badrenoceptors (i.e. b-less mice) and mice deficient in UCP1 show impaired thermogenesis and poor tolerance to cold exposure. [5][6][7] However, the findings that only the b-less mice, but not the UCP1-deficient mice, are highly susceptible to develop obesity have also underscored the existence, even in small rodents, of mechanisms other than the SNS-BAT-UCP1 ...