Transcriptional control of brown adipocyte development and thermogenesis

Seale, Patrick

doi:10.1038/ijo.2010.178

Cited by 40 publications

(37 citation statements)

References 53 publications

(39 reference statements)

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“…2C and 3B), whereas the Pde1b expression level, miR-378 proposed target, was inconsistent with increased miR-387 expression. In addition, the decreased expression of Rip140 could induce a broad spectrum of changes in brown-specific genes (38) by liberating restrictions on the nuclear receptors of Ppar␥, Ppar␣, C/ebp␤, and Prdm16 (39,40). Moreover, Rip140 plays an important role in anti-inflammation (41), which is well aligned with the immunomodulatory role of n-3 PUFA.…”

Section: Discussionmentioning

confidence: 99%

Eicosapentaenoic Acid Potentiates Brown Thermogenesis through FFAR4-dependent Up-regulation of miR-30b and miR-378

Kim

Okla

Erickson

et al. 2016

Journal of Biological Chemistry

101

120

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Emerging evidence suggests that n-3 polyunsaturated fatty acids (PUFA) promote brown adipose tissue thermogenesis. However, the underlying mechanisms remain elusive. Here, we hypothesize that n-3 PUFA promotes brown adipogenesis by modulating miRNAs. To test this hypothesis, murine brown preadipocytes were induced to differentiate the fatty acids of palmitic, oleate, or eicosapentaenoic acid (EPA). The increases of brown-specific signature genes and oxygen consumption rate by EPA were concurrent with up-regulation of miR-30b and 378 but not by oleate or palmitic acid. Next, we hypothesize that free fatty acid receptor 4 (Ffar4), a functional receptor for n-3 PUFA, modulates miR-30b and 378. Treatment of Ffar4 agonist (GW9508) recapitulated the thermogenic activation of EPA by increasing oxygen consumption rate, brown-specific marker genes, and miR-30b and 378, which were abrogated in Ffar4-silenced cells. Intriguingly, addition of the miR-30b mimic was unable to restore EPA-induced Ucp1 expression in Ffar4-depleted cells, implicating that Ffar4 signaling activity is required for up-regulating the brown adipogenic program. Moreover, blockage of miR-30b or 378 by locked nucleic acid inhibitors significantly attenuated Ffar4 as well as brown-specific signature gene expression, suggesting the signaling interplay between Ffar4 and miR-30b/378. The association between miR-30b/378 and brown thermogenesis was also confirmed in fish oil-fed C57/BL6 mice. Interestingly, the Ffar4 agonism-mediated signaling axis of Ffar4-miR-30b/378-Ucp1 was linked with an elevation of cAMP in brown adipocytes, similar to cold-exposed or fish oil-fed brown fat. Taken together, our work identifies a novel function of Ffar4 in modulating brown adipogenesis partly through a mechanism involving cAMP activation and upregulation of miR-30b and miR-378.There are two specific types of fat with opposite functions, brown adipose tissue (BAT) 3 and white adipose tissue (WAT).WAT stores energy in the form of triglyceride, whereas BAT dissipates energy in the form of heat via uncoupling protein 1 (UCP1) (1). Recent advances in our understanding of BAT biology in humans have provided a new insight into weight loss strategies by boosting BAT thermogenesis. Despite the surge of research for identifying cellular and molecular regulators of brown fat development (2, 3), the role of dietary constituents, particularly dietary fatty acids (FA), in thermogenic activation is poorly understood. Depending on the degree of desaturation and the n-6/n-3 ratio, FA differentially control adiposity, insulin sensitivity, immune response (4), and probably energy expenditure (5-7). Lately, it has been suggested that n-3 polyunsaturated FA (PUFA) stimulate beige/brown adipogenesis in primary murine adipogenic precursor cells (5) as well as C57BL/6 mice (6, 7). The latter animal study suggests that n-3 PUFA are associated with sympathetic activation and increased ␤3-adrenergic receptor (Adrb3) signaling (7). However, the underlying mechanistic details of how dietary n-3 PUFA...

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Section: Discussionmentioning

confidence: 99%

Eicosapentaenoic Acid Potentiates Brown Thermogenesis through FFAR4-dependent Up-regulation of miR-30b and miR-378

Kim

Okla

Erickson

et al. 2016

Journal of Biological Chemistry

101

120

View full text Add to dashboard Cite

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“…Therefore, the synthesis and/or degradation of the ligand(s) must be a key factor in this regulation. Although the exact identification of the biologically active oxysterols that function as LXR ligands is still unclear, 29 the enzymes involved in their production 30 and elimination 31,32 could have a key role. In light of this, it is interesting that the expression of cholesterol 25-hydroxylase, one of the enzymes of oxysterol synthesis, is approximately 30 times greater in white fat than in brown fat (see Supplementary data in Wang et al 28 ).…”

Section: Targetsmentioning

confidence: 99%

Positive and negative control of Ucp1 gene transcription and the role of β-adrenergic signaling networks

2010

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Adrenergic receptor signaling in adipocytes controls not only the hydrolysis of triglycerides as fuel for other organs but is also a driver of brown adipocyte thermogenesis and energy consumption. As the appearance of these mitochondria-rich, thermogenically active cells in 'white' adipocyte depots is correlated with resistance to overnutrition and glucose intolerance, the molecular basis of their genesis and metabolic activity needs to be understood. b-adrenergic receptors regulate the enzymatic machinery for lipolysis and fuel utilization. They also coordinately stimulate the transcription of genes that support the specific functions of white and brown adipocytes. They accomplish this through the activation of a network of signaling pathways that include cAMP-dependent protein kinase and members of the mitogen-activated protein kinase family. In brown adipocytes, these kinases control the transcription of nuclear factors such as peroxisome proliferator-activated receptor-g coactivator-1s, as well as other molecules discovered to respond to adrenergic signals, to increase mitochondrial biogenesis and uncoupling protein-1 (UCP1) expression. However, it is also important to understand the mechanisms that may actively repress these energy-wasting processes. Toward that end, we provide evidence for an important role for the nuclear receptor LXRa as a cAMP-and oxysterol-dependent transcriptional repressor of the Ucp1 gene. Adipocytes from LXRa-null mice have increased expression of most 'markers' of brown adipocytes, increased mitochondrial mass and uncoupled respiration. These studies reveal potential new targets and directions for controlling the relative levels of white versus brown adipocytes as a means of metabolic fuel utilization in the struggle against obesity and related metabolic diseases.

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“…Brown adipocytes in WAT express UCP1 and are histologically similar to BAT adipocytes. However, they do not have, as the latter, a myogenic origin (1,15,37,42,48). Their mitochondria exhibit enhanced ex vivo oxygen consumption following chronic adrenergic stimulation (16,43).…”

mentioning

confidence: 99%

Metabolic activity of brown, “beige,” and white adipose tissues in response to chronic adrenergic stimulation in male mice

Labbé

Caron

Chechi

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Classical brown adipocytes such as those found in interscapular brown adipose tissue (iBAT) represent energy-burning cells, which have been postulated to play a pivotal role in energy metabolism. Brown adipocytes can also be found in white adipose tissue (WAT) depots [e.g., inguinal WAT (iWAT)] following adrenergic stimulation, and they have been referred to as “beige” adipocytes. Whether the presence of these adipocytes, which gives iWAT a beige appearance, can confer a white depot with some thermogenic activity remains to be seen. In consequence, we designed the present study to investigate the metabolic activity of iBAT, iWAT, and epididymal white depots in mice. Mice were either 1) kept at thermoneutrality (30°C), 2) kept at 30°C and treated daily for 14 days with an adrenergic agonist [CL-316,243 (CL)], or 3) housed at 10°C for 14 days. Metabolic activity was assessed using positron emission tomography imaging with fluoro-[18F]deoxyglucose (glucose uptake), fluoro-[18F]thiaheptadecanoic acid (fatty acid uptake), and [11C]acetate (oxidative activity). In each group, substrate uptakes and oxidative activity were measured in anesthetized mice in response to acute CL. Our results revealed iBAT as a major site of metabolic activity, which exhibited enhanced glucose and nonesterified fatty acid uptakes and oxidative activity in response to chronic cold and CL. On the other hand, beige adipose tissue failed to exhibit appreciable increase in oxidative activity in response to chronic cold and CL. Altogether, our results suggest that the contribution of beige fat to acute-CL-induced metabolic activity is low compared with that of iBAT, even after sustained adrenergic stimulation.

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Transcriptional control of brown adipocyte development and thermogenesis

Cited by 40 publications

References 53 publications

Eicosapentaenoic Acid Potentiates Brown Thermogenesis through FFAR4-dependent Up-regulation of miR-30b and miR-378

Eicosapentaenoic Acid Potentiates Brown Thermogenesis through FFAR4-dependent Up-regulation of miR-30b and miR-378

Positive and negative control of Ucp1 gene transcription and the role of β-adrenergic signaling networks

Metabolic activity of brown, “beige,” and white adipose tissues in response to chronic adrenergic stimulation in male mice

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