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Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 293: E444-E452, 2007. First published May 1, 2007; doi: 10.1152/ajpendo.00691.2006.--The contention that brown adipose tissue is absent in adult man has meant that processes attributed to active brown adipose tissue in experimental animals (mainly rodents), i.e., classical nonshivering thermogenesis, adaptive adrenergic thermogenesis, diet-induced thermogenesis, and antiobesity, should be either absent or attributed to alternative (unknown) mechanisms in man. However, serendipidously, as a consequence of the use of fluorodeoxyglucose positron emission tomography (FDG PET) to trace tumor metastasis, observations that may change that notion have recently been made. These tomography scans have visualized symmetrical areas of increased tracer uptake in the upper parts of the human body; these areas of uptake correspond to brown adipose tissue. We examine here the published observations from a viewpoint of human physiology. The human depots are somewhat differently located from those in rodents, the main depots being found in the supraclavicular and the neck regions with some additional paravertebral, mediastinal, para-aortic, and suprarenal localizations (but no interscapular). Brown adipose tissue activity in man is acutely cold induced and is stimulated via the sympathetic nervous system. The prevalence of active brown adipose tissue in normal adult man can be only indirectly estimated, but it would seem that the prevalence of active brown adipose tissue in the population may be at least in the range of some tens of percent. We conclude that a substantial fraction of adult humans possess active brown adipose tissue that thus has the potential to be of metabolic significance for normal human physiology as well as to become pharmaceutically activated in efforts to combat obesity. fluorodesoxyglucose; positron emission tomography; glucose uptake; nonshivering thermogenesis

The biological role of beta3-adrenoceptors in guinea pig adipocytes after cold acclimation were analyzed by beta3-adrenoceptor gene cloning and sequencing. Treatment of beta3-adrenergic agonists on guinea pig brown and white adipocytes indicated the presence of functional beta3-adrenoceptors and beta3-adrenoceptor transcripts. Polymerase chain reaction-based assay also indicated the tissue-specific expression of the beta3-adrenoceptor gene which exhibits an amino acid sequence that is similar to human and bovine genes.

Experimental studies of the brown fat cells to determine whether the coexisting beta1-, beta3- and beta2- adrenoceptors contribute to the thermogenic response of the cells reveal that despite the coexistence, beta1- and beta2-adrenoceptors do not mediate thermogenic response and that only beta3-adrenoreceptor mediates thermiogenesis. BRL-37344, CGP-12177 and norepinephrine function through the beta3-adrenoreceptor to cause thermiogenesis. Beta-antagonists inhibit the CGP-12177- and BRL-37344-induced thermiogenesis in cells.

Prolonged supplementation with the β2-agonist clenbuterol improves glucose homeostasis in diabetic rodents, likely via β2-adrenoceptor (β2-AR)-mediated effects in the skeletal muscle and liver. However, since rodents have, in contrast to—especially diabetic—humans, substantial quantities of brown adipose tissue (BAT) and clenbuterol has affinity to β1- and β3-ARs, the contribution of BAT to these improvements is unclear. Therefore, we investigated clenbuterol-mediated improvements in glucose homeostasis in uncoupling protein 1-deficient (UCP1-/-) mice, lacking thermogenic BAT, versus wild-type (WT) mice. Anesthetized WT and UCP1-/- C57Bl/6 mice were injected with saline or clenbuterol and whole body oxygen consumption was measured. Furthermore, male WT and UCP1-/- C57Bl/6 mice were subjected to 17-wk of chow feeding, high-fat feeding, or high-fat feeding with clenbuterol treatment between weeks 13 and 17. Body composition was measured weekly with MRI. Oral glucose tolerance and insulin tolerance tests were performed in week 15 and 17, respectively. Clenbuterol increased oxygen consumption approximately twofold in WT mice. This increase was blunted in UCP1-/- mice, indicating clenbuterol-mediated activation of BAT thermogenesis. High-fat feeding induced diabetogenic phenotypes in both genotypes. However, low-dose clenbuterol treatment for 2 wk significantly reduced fasting blood glucose by 12.9% in WT and 14.8% in UCP1-/- mice. Clenbuterol treatment improved glucose and insulin tolerance in both genotypes compared with HFD controls and normalized to chow-fed control mice independent of body mass and composition alterations. Clenbuterol improved whole body glucose homeostasis independent of UCP1. Given the low human abundancy of BAT, β2-AR agonist treatment provides a potential novel route for glucose disposal in diabetic humans. NEW & NOTEWORTHY Improvements in whole body glucose homeostasis of rodents upon prolonged β2-adrenergic agonist supplementation could potentially be attributed to UCP1-mediated BAT thermogenesis. Indeed, we show that acute injection with the β2-AR agonist clenbuterol induces BAT activation in mice. However, we also demonstrate that prolonged clenbuterol supplementation robustly improves whole body glucose and insulin tolerance in a similar way in both DIO WT and UCP1-/- mice, indicating that β2-AR agonist supplementation improves whole body glucose homeostasis independent of UCP1-mediated BAT thermogenesis. [ABSTRACT FROM AUTHOR]

The type 2 diabetes epidemic makes it important to find insulin-independent ways to improve glucose homeostasis. This study examines the mechanisms activated by a dual β2-/β3-adrenoceptor agonist, BRL37344, to increase glucose uptake in skeletal muscle and its effects on glucose homeostasis in vivo. We measured the effect of BRL37344 on glucose uptake, glucose transporter 4 (GLUT4) translocation, cAMP levels, β2-adrenoceptor desensitization, β-arrestin recruitment, Akt, AMPK, and mammalian target of rapamycin (mTOR) phosphorylation using L6 skeletal muscle cells as a model. We further tested the ability of BRL37344 to modulate skeletal muscle glucose metabolism in animal models (glucose tolerance tests and in vivo and ex vivo skeletal muscle glucose uptake). In L6 cells, BRL37344 increased GLUT4 translocation and glucose uptake only by activation of β2-adrenoceptors, with a similar potency and efficacy to that of the nonselective β-adrenoceptor agonist isoprenaline, despite being a partial agonist with respect to cAMP generation. GLUT4 translocation occurred independently of Akt and AMPK phosphorylation but was dependent on mTORC2. Furthermore, in contrast to isoprenaline, BRL37344 did not promote agonist-mediated desensitization and failed to recruit β-arrestin1/2 to the β2-adrenoceptor. In conclusion, BRL37344 improved glucose tolerance and increased glucose uptake into skeletal muscle in vivo and ex vivo through a β2-adrenoceptor-mediated mechanism independently of Akt. BRL37344 was a partial agonist with respect to cAMP, but a full agonist for glucose uptake, and importantly did not cause classical receptor desensitization or internalization of the receptor. [ABSTRACT FROM AUTHOR]

The pathway for adrenergic relaxation of smooth muscle is not fully understood. As mitochondrial uncoupling protein-1 (UCP1) expression has been reported in cells within the longitudinal smooth muscle layer of organs exhibiting peristalsis, we examined whether the absence of UCP1 affects adrenergic responsiveness. Intestinal (ileal) segments were obtained from UCP1-ablated mice and from wild-type mice (C57Bl/6, 129/SvPas, and outbred NMRI). In UCP1-containing mice, isoprenaline totally inhibited contractions induced by electrical field stimulation, but in intestine from UCP1-ablated mice, a significant residual contraction remained even at a high isoprenaline concentration; the segments were threefold less sensitive to isoprenaline. Also, when contraction was induced by carbachol, there was a residual isoprenaline-insensitive contraction. Similar results were obtained with the [[beta].sup.3]-selective agonist CL-316,243 and with the adenylyl cyclase stimulator forskolin. Thus the UCP1 reported to be expressed in the longitudinal muscle layer of the mouse intestine is apparently functional, and UCP1, presumably through uncoupling, may be involved in a novel pathway leading from increased cAMP levels to relaxation in organs exhibiting peristalsis. carbachol; isoprenaline; forskolin

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 function were investigated. β3-knockout mice were able to survive both acute and prolonged cold exposure due to activation of β1-adrenergic receptors. Thus, in the absence of β3-adrenergic receptors, β1-adrenergic receptors are effectively able to signal via cAMP to elicit cAMP-mediated responses and to recruit and activate brown adipose tissue. In addition, we found that in human multipotent adipose-derived stem cells differentiated into functional brown adipocytes, activation of either β1-adrenergic receptors or β3-adrenergic receptors was able to increase UCP1 mRNA and protein levels. Thus, in humans, β1-adrenergic receptors could play an important role in regulating nonshivering thermogenesis. [ABSTRACT FROM AUTHOR]