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Non-sympathetic control of brown adipose tissue.

ABSTRACT: The thermogenic activity of brown adipose tissue (BAT) in the organism is tightly regulated through different processes, from short-term induction of uncoupling protein-1-mediated mitochondrial proton conductance to complex processes of BAT recruitment, and appearance of the beige/brite adipocytes in white adipose tissue (WAT), the so-called browning process. The sympathetic nervous system is classically recognized as the main mediator of BAT activation. However, novel factors capable of activating BAT through non-sympathetic mechanisms have been recently identified. Among them are members of the bone morphogenetic protein family, with likely autocrine actions, and activators of nuclear hormone receptors, especially vitamin A derivatives. Multiple endocrine factors released by peripheral tissues that act on BAT have also been identified. Some are natriuretic peptides of cardiac origin, whereas others include irisin, originating in skeletal muscle, and fibroblast growth factor-21, mainly produced in the liver. These factors have cell-autonomous effects in brown adipocytes, but indirect effects in vivo that modulate sympathetic activity toward BAT cannot be excluded. Moreover, these factors can affect to different extents such as the activation of existing BAT, the induction of browning in WAT or both. The identification of non-sympathetic controllers of BAT activity is of special biomedical interest as a prerequisite for developing pharmacological tools that influence BAT activity without the side effects of sympathomimetics.

SUBMITTER: Cereijo R

PROVIDER: S-EPMC4850569 | biostudies-other | 2015 Aug

REPOSITORIES: biostudies-other

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Project description:Obesity is the principal symptom of metabolic syndrome, which refers to a group of risk factors that increase the likelihood of atherosclerosis. In recent decades there has been a sharp rise in the incidence of obesity throughout the developed world. Iso-α-acids, the bitter compounds derived from hops in beer, have been shown to prevent diet-induced obesity by increasing lipid oxidation in the liver and inhibition of lipid absorption from the intestine. Whereas the sharp bitterness induced by effective dose of iso-α-acids precludes their acceptance as a nutrient, matured hop bittering components (MHB) appear to be more agreeable. Therefore, we tested MHB for an effect on ameliorating diet-induced body fat accumulation in rodents. MHB ingestion had a beneficial effect but, compared to iso-α-acids and despite containing structurally similar compounds, acted via different mechanisms to reduce body fat accumulation. MHB supplementation significantly reduced body weight gain, epididymal white adipose tissue weight, and plasma non-esterified free fatty acid levels in diet-induced obese mice. We also found that uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT) was significantly increased in MHB-fed mice at both the mRNA and protein levels. In addition, MHB administration in rats induced the β-adrenergic signaling cascade, which is related to cAMP accumulation in BAT, suggesting that MHB could modulate sympathetic nerve activity innervating BAT (BAT-SNA). Indeed, single oral administration of MHB elevated BAT-SNA in rats, and this elevation was dissipated by subdiaphragmatic vagotomy. Single oral administration of MHB maintained BAT temperature at a significantly higher level than in control rats. Taken together, these findings indicate that MHB ameliorates diet-induced body fat accumulation, at least partly, by enhancing thermogenesis in BAT via BAT-SNA activation. Our data suggests that MHB is a useful tool for developing functional foods or beverages to counteract the accumulation of body fat.

Project description:ObjectiveThe objective of this study was to functionally analyze the correlation of key histological features in brown adipose tissue (BAT) with clinical metabolic traits in nonhuman primates.MethodsAxillary adipose tissue biopsies were collected from a metabolically diverse nonhuman primate cohort with clinical metabolism-related data. Expression of tyrosine hydroxylase (TH), uncoupling protein 1 (UCP1), cluster of differentiation 31 (CD31), cytochrome c oxidase subunit 4 (COX IV), beta-3 adrenergic receptor (β3-AR), and adipose cell size were quantified by immunohistochemical analysis. Computed tomography scans were performed to assess body composition.ResultsTyrosine hydroxylase was negatively correlated with whole body fat mass as a percentage of body weight (p = 0.004) and was positively correlated with the density of UCP1 (p = 0.02), COX IV (p = 0.006), CD31 (p = 0.007), and cell density (p = 0.02) of the BAT samples. Beta-3 adrenergic receptor abundance had a weak positive correlation with COX IV (p = 0.04) in BAT but did not significantly correlate to UCP1 or TH expression in BAT.ConclusionsOur findings highlight that there is a disparity in innervation provided to BAT based on body composition, as seen with the negative association between TH, a marker for innervation, and adiposity. These findings also support the importance of innervation in the functionality of BAT, as TH abundance not only supports leaner body composition but is also positively correlated with known structural elements in BAT (UCP1, COX IV, CD31, and cell density). Based on our observations, β3-AR abundance does not strongly drive these structural elements or TH, all of which are known to be important in the function of brown adipose tissue. In effect, while the role of other receptors, such as β2-AR, should be reviewed in BAT function, these results support the development of safe sympathetic nervous system stimulants to activate brown adipose tissue for obesity treatment.

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Non-sympathetic control of brown adipose tissue.

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