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The miR-182-5p/FGF21/acetylcholine axis mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis.

ABSTRACT: A dynamically regulated microenvironment, which is mediated by crosstalk between adipocytes and neighboring cells, is critical for adipose tissue homeostasis and function. However, information on key molecules and/or signaling pathways regulating the crosstalk remains limited. In this study, we identify adipocyte miRNA-182-5p (miR-182-5p) as a crucial antiobesity molecule that stimulated beige fat thermogenesis by promoting the crosstalk between adipocytes and macrophages. miR-182-5p was highly enriched in thermogenic adipocytes, and its expression was markedly stimulated by cold exposure in mice. In contrast, miR-182-5p expression was significantly reduced in adipose tissues of obese humans and mice. Knockout of miR-185-5p decreased cold-induced beige fat thermogenesis whereas overexpression of miR-185-5p increased beiging and thermogenesis in mice. Mechanistically, miR-182-5p promoted FGF21 expression and secretion in adipocytes by suppressing nuclear receptor subfamily 1 group D member 1 (Nr1d1) at 5'-UTR, which in turn stimulates acetylcholine synthesis and release in macrophages. Increased acetylcholine expression activated the nicotine acetylcholine receptor in adipocytes, which stimulated PKA signaling and consequent thermogenic gene expression. Our study reveals a key role of the miR-182-5p/FGF21/acetylcholine/acetylcholine receptor axis that mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis. Activation of the miR-182-5p-induced signaling pathway in adipose tissue may be an effective approach to ameliorate obesity and associated metabolic diseases.

SUBMITTER: Meng W

PROVIDER: S-EPMC8492300 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The miR-182-5p/FGF21/acetylcholine axis mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis

Project description:The miR-182-5p/FGF21/acetylcholine axis mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis miR182 overexpression in primary cultured iWAT

2021-10-13 | GSE178952 | GEO

The miR-182-5p/FGF21/acetylcholine axis mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis

Project description:The miR-182-5p/FGF21/acetylcholine axis mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis

| PRJNA741665 | ENA

FGF21 mimetic antibody stimulates UCP1-independent brown fat thermogenesis via FGFR1/?Klotho complex in non-adipocytes.

Project description:OBJECTIVE:Fibroblast Growth Factor 21 (FGF21) is a potent stimulator of brown fat thermogenesis that improves insulin sensitivity, ameliorates hepatosteatosis, and induces weight loss by engaging the receptor complex comprised of Fibroblast Growth Factor Receptor 1 (FGFR1) and the requisite coreceptor ?Klotho. Previously, recombinant antibody proteins that activate the FGFR1/?Klotho complex were proposed to act as an FGF21-mimetic; however, in vivo action of these engineered proteins has not been well studied. METHODS:We investigated the mechanism by which anti-FGFR1/?Klotho bispecific antibody (bFKB1) stimulates thermogenesis in UCP1-expressing brown adipocytes using genetically engineered mice. Anti-FGFR1 agonist antibody was also used to achieve brown adipose tissue restricted activation in transgenic mice. RESULTS:Studies with global Ucp1-deficient mice and adipose-specific Fgfr1 deficient mice demonstrated that bFKB1 acts on targets distal to adipocytes and indirectly stimulates brown adipose thermogenesis in a UCP1-independent manner. Using a newly developed transgenic system, we also show that brown adipose tissue restricted activation of a transgenic FGFR1 expressed under the control of Ucp1 promoter does not stimulate energy expenditure. Finally, consistent with its action as a FGF21 mimetic, bFBK1 suppresses intake of saccharin-containing food and alcohol containing water in mice. CONCLUSIONS:Collectively, we propose that FGFR1/?Klotho targeted therapy indeed mimics the action of FGF21 in vivo and stimulates UCP1-independent brown fat thermogenesis through receptors outside of adipocytes and likely in the nervous system.

| S-EPMC5681280 | biostudies-literature

UCP1 Dependent and Independent Thermogenesis in Brown and Beige Adipocytes.

Project description:Mammals have two types of thermogenic adipocytes: brown adipocytes and beige adipocytes. Thermogenic adipocytes express high levels of uncoupling protein 1 (UCP1) to dissipates energy in the form of heat by uncoupling the mitochondrial proton gradient from mitochondrial respiration. There is much evidence that UCP1 is the center of BAT thermogenesis and systemic energy homeostasis. Recently, UCP1 independent thermogenic pathway identified in thermogenic adipocytes. Importantly, the thermogenic pathways are different in brown and beige adipocytes. Ca2+-ATPase 2b calcium cycling mechanism is selective to beige adipocytes. It remains unknown how the multiple thermogenic mechanisms are coordinately regulated. The discovery of UCP1-independent thermogenic mechanisms potential offer new opportunities for improving obesity and type 2 diabetes particularly in groups such as elderly and obese populations who do not possess UCP1 positive adipocytes.

| S-EPMC7399049 | biostudies-literature

Editorial: Novel regulatory mechanisms behind thermogenesis of brown and beige adipocytes.

Project description: Not available

| S-EPMC10471955 | biostudies-literature

Endothelial PDGF-CC regulates angiogenesis-dependent thermogenesis in beige fat.

Project description:Cold- and β3-adrenoceptor agonist-induced sympathetic activation leads to angiogenesis and UCP1-dependent thermogenesis in mouse brown and white adipose tissues. Here we show that endothelial production of PDGF-CC during white adipose tissue (WAT) angiogenesis regulates WAT browning. We find that genetic deletion of endothelial VEGFR2, knockout of the Pdgf-c gene or pharmacological blockade of PDGFR-α impair the WAT-beige transition. We further show that PDGF-CC stimulation upregulates UCP1 expression and acquisition of a beige phenotype in differentiated mouse WAT-PDGFR-α(+) progenitor cells, as well as in human WAT-PDGFR-α(+) adipocytes, supporting the physiological relevance of our findings. Our data reveal a paracrine mechanism by which angiogenic endothelial cells modulate adipocyte metabolism, which may provide new targets for the treatment of obesity and related metabolic diseases.

| S-EPMC4980448 | biostudies-literature

MiR-494-3p regulates mitochondrial biogenesis and thermogenesis through PGC1-? signalling in beige adipocytes.

Project description:Mitochondria are critical in heat generation in brown and beige adipocytes. Mitochondrial number and function are regulated in response to external stimuli, such as cold exposure and ?3 adrenergic receptor agonist. However, the molecular mechanisms regulating mitochondrial biogenesis during browning, especially by microRNAs, remain unknown. We investigated the role of miR-494-3p in mitochondrial biogenesis during adipogenesis and browning. Intermittent mild cold exposure of mice induced PPAR? coactivator1-? (PGC1-?) and mitochondrial TFAM, PDH, and ANT1/2 expression along with uncoupling protein-1 (Ucp1) in inguinal white adipose tissue (iWAT). miR-494-3p levels were significantly downregulated in iWAT upon cold exposure (p?<?0.05). miR-494-3p overexpression substantially reduced PGC1-? expression and its downstream targets TFAM, PDH and MTCO1 in 3T3-L1 white and beige adipocytes (p?<?0.05). miR-494-3p inhibition in 3T3-L1 white adipocytes resulted in increased PDH (p?<?0.05). PGC1-?, TFAM and Ucp1 mRNA levels were robustly downregulated by miR-494-3p overexpression in 3T3-L1 beige adipocytes, along with strongly decreased oxygen consumption rate. PGC1-? and Ucp1 proteins were downregulated by miR-494-3p in primary beige cells (p?<?0.05). Luciferase assays confirmed PGC1-? as a direct gene target of miR-494-3p. Our findings demonstrate that decreased miR-494-3p expression during browning regulates mitochondrial biogenesis and thermogenesis through PGC1-?.

| S-EPMC6180067 | biostudies-literature

Breast milk alkylglycerols sustain beige adipocytes through adipose tissue macrophages.

Project description:Prevalence of obesity among infants and children below 5 years of age is rising dramatically, and early childhood obesity is a forerunner of obesity and obesity-associated diseases in adulthood. Childhood obesity is hence one of the most serious public health challenges today. Here, we have identified a mother-to-child lipid signaling that protects from obesity. We have found that breast milk-specific lipid species, so-called alkylglycerol-type (AKG-type) ether lipids, which are absent from infant formula and adult-type diets, maintain beige adipose tissue (BeAT) in the infant and impede the transformation of BeAT into lipid-storing white adipose tissue (WAT). Breast milk AKGs are metabolized by adipose tissue macrophages (ATMs) to platelet-activating factor (PAF), which ultimately activates IL-6/STAT3 signaling in adipocytes and triggers BeAT development in the infant. Accordingly, lack of AKG intake in infancy leads to a premature loss of BeAT and increases fat accumulation. AKG signaling is specific for infants and is inactivated in adulthood. However, in obese adipose tissue, ATMs regain their ability to metabolize AKGs, which reduces obesity. In summary, AKGs are specific lipid signals of breast milk that are essential for healthy adipose tissue development.

| S-EPMC6546455 | biostudies-literature

Beige Fat, Adaptive Thermogenesis, and Its Regulation by Exercise and Thyroid Hormone.

Project description:While it is now understood that the proper expansion of adipose tissue is critically important for metabolic homeostasis, it is also appreciated that adipose tissues perform far more functions than simply maintaining energy balance. Adipose tissue performs endocrine functions, secreting hormones or adipokines that affect the regulation of extra-adipose tissues, and, under certain conditions, can also be major contributors to energy expenditure and the systemic metabolic rate via the activation of thermogenesis. Adipose thermogenesis takes place in brown and beige adipocytes. While brown adipocytes have been relatively well studied, the study of beige adipocytes has only recently become an area of considerable exploration. Numerous suggestions have been made that beige adipocytes can elicit beneficial metabolic effects on body weight, insulin sensitivity, and lipid levels. However, the potential impact of beige adipocyte thermogenesis on systemic metabolism is not yet clear and an understanding of beige adipocyte development and regulation is also limited. This review will highlight our current understanding of beige adipocytes and select factors that have been reported to elicit the development and activation of thermogenesis in beige cells, with a focus on factors that may represent a link between exercise and 'beiging', as well as the role that thyroid hormone signaling plays in beige adipocyte regulation.

| S-EPMC6783838 | biostudies-literature

Glucocorticoid/Adiponectin Axis Mediates Full Activation of Cold-Induced Beige Fat Thermogenesis.

Project description:Glucocorticoids (GCs), a class of corticosteroids produced by the adrenal cortex in response to stress, exert obesity-promoting effects. Although adaptive thermogenesis has been considered an effective approach to counteract obesity, whether GCs play a role in regulating cold stress-induced thermogenesis remains incompletely understood. Here, we show that the circulating levels of stress hormone corticosterone (GC in rodents) were significantly elevated, whereas the levels of adiponectin, an adipokine that was linked to cold-induced adaptive thermogenesis, were decreased 48 h post cold exposure. The administration of a glucocorticoid hydrocortisone downregulated adiponectin protein and mRNA levels in both WAT and white adipocytes, and upregulated thermogenic gene expression in inguinal fat. In contrast, mifepristone, a glucocorticoid receptor antagonist, enhanced adiponectin expression and suppressed energy expenditure in vivo. Mechanistically, hydrocortisone suppressed adiponectin expression by antagonizing PPARγ in differentiated 3T3-L1 adipocytes. Ultimately, adiponectin deficiency restored mifepristone-decreased oxygen consumption and suppressed the expression of thermogenic genes in inguinal fat. Taken together, our study reveals that the GCs/adiponectin axis is a key regulator of beige fat thermogenesis in response to acute cold stress.

| S-EPMC8615797 | biostudies-literature

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