Foxp1 controls brown/beige adipocyte differentiation and thermogenesis through regulating β3-AR desensitization

Abstract β-Adrenergic receptor (β-AR) signaling is a pathway controlling adaptive thermogenesis in brown or beige adipocytes. Here we investigate the biological roles of the transcription factor Foxp1 in brown/beige adipocyte differentiation and thermogenesis. Adipose-specific deletion of Foxp1 leads to an increase of brown adipose activity and browning program of white adipose tissues. The Foxp1-deficient mice show an augmented energy expenditure and are protected from diet-induced obesity and insulin resistance. Consistently, overexpression of Foxp1 in adipocytes impairs adaptive thermogenesis and promotes diet-induced obesity. A robust change in abundance of the β3-adrenergic receptor (β3-AR) is observed in brown/beige adipocytes from both lines of mice. Molecularly, Foxp1 directly represses β3-AR transcription and regulates its desensitization behavior. Taken together, our findings reveal Foxp1 as a master transcriptional repressor of brown/beige adipocyte differentiation and thermogenesis, and provide an important clue for its targeting and treatment of obesity.

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Mfsd2a encodes a novel major facilitator superfamily domain-containing protein highly induced in brown adipose tissue during fasting and adaptive thermogenesis

Biochemical Journal ◽

10.1042/bj20080165 ◽

2008 ◽

Vol 416 (3) ◽

pp. 347-355 ◽

Cited By ~ 43

Author(s):

Martin Angers ◽

Marc Uldry ◽

Dong Kong ◽

Jeffrey M. Gimble ◽

Anton M. Jetten

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Adrenergic Receptor ◽

Common Ancestor ◽

Major Facilitator Superfamily ◽

Adaptive Thermogenesis ◽

Brown Adipose ◽

Exon Junctions ◽

Major Facilitator ◽

Deficient Mice

This study describes the identification of Mfsd2a (major facilitator superfamily domain-containing protein 2a), a novel mammalian major facilitator superfamily domain-containing protein, and an additional closely related protein, Mfsd2b. Most intron/exon junctions are conserved between the two genes, suggesting that they are derived from a common ancestor. Mfsd2a and Mfsd2b share a 12 transmembrane α-helical domain structure that bears greatest similarity to that of the bacterial Na+/melibiose symporters. Confocal microscopy demonstrated that Mfsd2a localizes to the endoplasmic reticulum. Mfsd2a is expressed in many tissues and is highly induced in liver and BAT (brown adipose tissue) during fasting. Mfsd2a displays an oscillatory expression profile in BAT and liver, consistent with a circadian rhythm. Although the basal level of Mfsd2a expression is relatively low in mouse BAT, it is greatly induced during cold-induced thermogenesis and after treatment with βAR (β-adrenergic receptor) agonists. This induction is totally abolished in β-less (βAR-deficient) mice. These findings indicate that Mfsd2a is greatly up-regulated in BAT during thermogenesis and that its induction is controlled by the βAR signalling pathway. The observed induction of Mfsd2a expression in cultured BAT cells by dibutyryl-cAMP is in agreement with this conclusion. The present study suggests that Mfsd2a plays a role in adaptive thermogenesis.

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HDAC11 Suppresses the Thermogenic Program of Adipose Tissue via BRD2

10.1101/292011 ◽

2018 ◽

Author(s):

Rushita A. Bagchi ◽

Bradley S. Ferguson ◽

Matthew S. Stratton ◽

Tianjing Hu ◽

Maria A. Cavasin ◽

...

Keyword(s):

Adipose Tissue ◽

Adrenergic Receptor ◽

Energy Homeostasis ◽

Biological Function ◽

Ex Vivo ◽

Obesity And Diabetes ◽

Brown Adipose ◽

Treatment Of Obesity ◽

Fat Feeding ◽

Deficient Mice

AbstractLittle is known about the biological function of histone deacetylase 11 (HDAC11), which is the lone class IV HDAC. Here, we demonstrate that deletion of HDAC11 in mice stimulates brown adipose tissue (BAT) formation and beiging of white adipose tissue (WAT). Consequently, HDAC11-deficient mice exhibit dramatically enhanced thermogenic potential and, in response to high fat feeding, attenuated obesity, insulin resistance, and hepatic steatosis. Ex vivo and cell-based assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to β-adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone binding protein. These findings define a novel epigenetic pathway for the regulation of energy homeostasis, and suggest potential for HDAC11-selective inhibitors for the treatment of obesity and diabetes.

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Effects of stem cells from inducible brown adipose tissue on diet-induced obesity in mice

Scientific Reports ◽

10.1038/s41598-021-93224-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Enrique Calvo ◽

Noelia Keiran ◽

Catalina Núñez-Roa ◽

Elsa Maymó-Masip ◽

Miriam Ejarque ◽

...

Keyword(s):

Stem Cells ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Therapeutic Option ◽

Metabolic Activation ◽

Diet Induced Obesity ◽

Brown Adipose ◽

Obesity In Mice ◽

Treatment Of Obesity ◽

Visceral Adipose

AbstractAdipose-derived mesenchymal stem cells (ASCs) are a promising option for the treatment of obesity and its metabolic co-morbidities. Despite the recent identification of brown adipose tissue (BAT) as a potential target in the management of obesity, the use of ASCs isolated from BAT as a therapy for patients with obesity has not yet been explored. Metabolic activation of BAT has been shown to have not only thermogenic effects, but it also triggers the secretion of factors that confer protection against obesity. Herein, we isolated and characterized ASCs from the visceral adipose tissue surrounding a pheochromocytoma (IB-hASCs), a model of inducible BAT in humans. We then compared the anti-obesity properties of IB-hASCs and human ASCs isolated from visceral white adipose tissue (W-hASCs) in a murine model of diet-induced obesity. We found that both ASC therapies mitigated the metabolic abnormalities of obesity to a similar extent, including reducing weight gain and improving glucose tolerance. However, infusion of IB-hASCs was superior to W-hASCs in suppressing lipogenic and inflammatory markers, as well as preserving insulin secretion. Our findings provide evidence for the metabolic benefits of visceral ASC infusion and support further studies on IB-hASCs as a therapeutic option for obesity-related comorbidities.

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Adipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue

10.1101/2020.06.06.137273 ◽

2020 ◽

Author(s):

Xin Cui ◽

Jia Jing ◽

Rui Wu ◽

Qiang Cao ◽

Fenfen Li ◽

...

Keyword(s):

Adipose Tissue ◽

Neurotrophic Factor ◽

Sympathetic Innervation ◽

Neurite Growth ◽

Sympathetic Neuron ◽

Beige Adipocyte ◽

Diet Induced Obesity ◽

Neurotrophin 3 ◽

Beige Adipocytes ◽

Adipocyte Development

AbstractActivation of brown fat thermogenesis increases energy expenditure and alleviates obesity. Sympathetic nervous system (SNS) is important in brown/beige adipocyte thermogenesis. Here we discover a novel fat-derived “adipokine” neurotrophic factor neurotrophin 3 (NTF3) and its receptor Tropomyosin receptor kinase C (TRKC) as key regulators of SNS growth and innervation in adipose tissue. NTF3 is highly expressed in brown/beige adipocytes, and potently stimulates sympathetic neuron neurite growth. NTF3/TRKC regulates a plethora of pathways in neuronal axonal growth and elongation. Adipose tissue sympathetic innervation is significantly increased in mice with adipocyte-specific NTF3 overexpression, but profoundly reduced in mice with TRKC haploinsufficiency (TRKC+/-). Increasing NTF3 via pharmacological or genetic approach promotes beige adipocyte development, enhances cold-induced thermogenesis and protects against diet-induced obesity (DIO); whereas TRKC+/- mice or SNS TRKC deficient mice are cold intolerant and prone to DIO. Thus, NTF3 is an important fat-derived neurotrophic factor regulating SNS innervation, energy metabolism and obesity.

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

Biology ◽

10.3390/biology8030057 ◽

2019 ◽

Vol 8 (3) ◽

pp. 57 ◽

Cited By ~ 6

Author(s):

Kevin J. Phillips

Keyword(s):

Adipose Tissue ◽

Thyroid Hormone ◽

Metabolic Effects ◽

Adipose Tissues ◽

Beige Adipocyte ◽

Adaptive Thermogenesis ◽

Beige Adipocytes ◽

Beige Fat ◽

Beige Cells ◽

Adipocyte Development

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.

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The Antiobesity Effects of Centrally Administered Neuromedin U and Neuromedin S Are Mediated Predominantly by the Neuromedin U Receptor 2 (NMUR2)

Endocrinology ◽

10.1210/en.2008-1772 ◽

2009 ◽

Vol 150 (7) ◽

pp. 3101-3109 ◽

Cited By ~ 47

Author(s):

Andrea Peier ◽

Jennifer Kosinski ◽

Kimberly Cox-York ◽

Ying Qian ◽

Kunal Desai ◽

...

Keyword(s):

Food Intake ◽

Energy Homeostasis ◽

Central Administration ◽

Diet Induced Obesity ◽

Inhibit Food Intake ◽

Selective Agonists ◽

Treatment Of Obesity ◽

The Brain ◽

Deficient Mice

Neuromedin U (NMU) and neuromedin S (NMS) are structurally related neuropeptides that have been reported to modulate energy homeostasis. Pharmacological data have shown that NMU and NMS inhibit food intake when administered centrally and that NMU increases energy expenditure. Additionally, NMU-deficient mice develop obesity, whereas transgenic mice overexpressing NMU are lean and hypophagic. Two high-affinity NMU/NMS receptors, NMUR1 and NMUR2, have been identified. NMUR1 is predominantly expressed in the periphery, whereas NMUR2 is predominantly expressed in the brain, suggesting that the effects of centrally administered NMU and NMS are mediated by NMUR2. To evaluate the role of NMUR2 in the regulation of energy homeostasis, we characterized NMUR2-deficient (Nmur2−/−) mice. Nmur2−/− mice exhibited a modest resistance to diet-induced obesity that was at least in part due to reduced food intake. Acute central administration of NMU and NMS reduced food intake in wild-type but not in Nmur2−/− mice. The effects on activity and core temperature induced by centrally administered NMU were also absent in Nmur2−/− mice. Moreover, chronic central administration of NMU and NMS evoked significant reductions in body weight and sustained reductions in food intake in mice. In contrast, Nmur2−/− mice were largely resistant to these effects. Collectively, these data demonstrate that the anorectic and weight-reducing actions of centrally administered NMU and NMS are mediated predominantly by NMUR2, suggesting that NMUR2-selective agonists may be useful for the treatment of obesity.

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Egr1 loss-of-function promotes beige adipocyte differentiation and activation specifically in inguinal subcutaneous white adipose tissue

Scientific Reports ◽

10.1038/s41598-020-72698-w ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Marianne Bléher ◽

Berbang Meshko ◽

Isabelle Cacciapuoti ◽

Rachel Gergondey ◽

Yoann Kovacs ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Adipocyte Differentiation ◽

Uncoupling Protein ◽

Subcutaneous Fat ◽

Loss Of Function ◽

Beige Adipocyte ◽

Subcutaneous White Adipose Tissue ◽

Fat Depots ◽

Beige Adipocytes

Abstract In mice, exercise, cold exposure and fasting lead to the differentiation of inducible-brown adipocytes, called beige adipocytes, within white adipose tissue and have beneficial effects on fat burning and metabolism, through heat production. This browning process is associated with an increased expression of the key thermogenic mitochondrial uncoupling protein 1, Ucp1. Egr1 transcription factor has been described as a regulator of white and beige differentiation programs, and Egr1 depletion is associated with a spontaneous increase of subcutaneous white adipose tissue browning, in absence of external stimulation. Here, we demonstrate that Egr1 mutant mice exhibit a restrained Ucp1 expression specifically increased in subcutaneous fat, resulting in a metabolic shift to a more brown-like, oxidative metabolism, which was not observed in other fat depots. In addition, Egr1 is necessary and sufficient to promote white and alter beige adipocyte differentiation of mouse stem cells. These results suggest that modulation of Egr1 expression could represent a promising therapeutic strategy to increase energy expenditure and to restrain obesity-associated metabolic disorders.

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Brown adipose tissue is the key depot for glucose clearance in microbiota depleted mice

Nature Communications ◽

10.1038/s41467-021-24659-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Min Li ◽

Li Li ◽

Baoguo Li ◽

Catherine Hambly ◽

Guanlin Wang ◽

...

Keyword(s):

Adipose Tissue ◽

Gut Microbiota ◽

Brown Adipose Tissue ◽

Glucose Uptake ◽

White Adipose Tissue ◽

Uncoupling Protein ◽

Adaptive Thermogenesis ◽

Brown Adipose ◽

Glucose Clearance ◽

Deficient Mice

AbstractGut microbiota deficient mice demonstrate accelerated glucose clearance. However, which tissues are responsible for the upregulated glucose uptake remains unresolved, with different studies suggesting that browning of white adipose tissue, or modulated hepatic gluconeogenesis, may be related to enhanced glucose clearance when the gut microbiota is absent. Here, we investigate glucose uptake in 22 different tissues in 3 different mouse models. We find that gut microbiota depletion via treatment with antibiotic cocktails (ABX) promotes glucose uptake in brown adipose tissue (BAT) and cecum. Nevertheless, the adaptive thermogenesis and the expression of uncoupling protein 1 (UCP1) are dispensable for the increased glucose uptake and clearance. Deletion of Ucp1 expressing cells blunts the improvement of glucose clearance in ABX-treated mice. Our results indicate that BAT and cecum, but not white adipose tissue (WAT) or liver, contribute to the glucose uptake in the gut microbiota depleted mouse model and this response is dissociated from adaptive thermogenesis.

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FOXP4 differentially controls cold-induced beige adipocyte differentiation and thermogenesis

10.1101/2021.10.11.463898 ◽

2021 ◽

Author(s):

Fuhua Wang ◽

Shuqin Xu ◽

Tienan Chen ◽

Shifeng Ling ◽

Wei Zhang ◽

...

Keyword(s):

Cell Fate ◽

Transcriptional Repression ◽

Adipocyte Differentiation ◽

Brown Adipocytes ◽

Beige Adipocyte ◽

Forkhead Box ◽

Beige Adipocytes ◽

Adipocyte Cell ◽

Adipocyte Development ◽

Fibroblastic Cells

Beige adipocytes possess a discrete developmental origin and notable plasticity in thermogenic capacity in response to various environmental cues. But the transcriptional machinery controlling beige adipocyte development and thermogenesis remains largely unknown. By analyzing beige adipocyte-specific knockout mice, we identified a transcription factor, Forkhead Box P4 (FOXP4) that differentially governs beige adipocyte differentiation and activation. Depletion of Foxp4 caused a decline in the frequency of beige preadipocytes by switching their cell fate towards fibroblastic cells at the expense of beige adipocytes. However, we observed that ablation of Foxp4 in differentiated adipocytes profoundly potentiated their thermogenesis upon cold exposure. Of note, the outcome of Foxp4-deficiency on UCP1-mediated thermogenesis was confined to beige adipocytes, rather than to brown adipocytes. Taken together, we submit that FOXP4 primes beige adipocyte cell fate commitment and differentiation by potent transcriptional repression of the thermogenic program.

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Egr1 loss-of-function promotes beige adipocyte differentiation and activation specifically in inguinal subcutaneous white adipose tissue

10.1101/2020.06.03.131342 ◽

2020 ◽

Author(s):

Marianne Bléher ◽

Berbang Meshko ◽

Rachel Gergondey ◽

Yoann Kovacs ◽

Delphine Duprez ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Adipocyte Differentiation ◽

Uncoupling Protein ◽

Subcutaneous Fat ◽

Loss Of Function ◽

Beige Adipocyte ◽

Subcutaneous White Adipose Tissue ◽

Fat Depots ◽

Beige Adipocytes

AbstractExercise, cold exposure and fasting lead to the differentiation of inducible-brown adipocytes, called beige adipocytes, within white adipose tissue and have beneficial effects on fat burning and metabolism, through heat production. This browning process is associated with an increased expression of the key thermogenic mitochondrial uncoupling protein 1, Ucp1. Egr1 transcription factor has been described as a regulator of white and beige differentiation programs, and Egr1 depletion is associated with a spontaneous increase of subcutaneous white adipose tissue browning, in absence of external stimulation. Here, we demonstrate that Egr1 mutant mice exhibit a restrained Ucp1 expression specifically increased in subcutaneous fat, resulting in a metabolic shift to a more brown-like, oxidative metabolism, which was not observed in other fat depots. In addition, Egr1 is necessary and sufficient to promote white and alter beige adipocyte differentiation of mouse stem cells. These results suggest that modulation of Egr1 expression could represent a promising therapeutic strategy to increase energy expenditure and to restrain obesity-associated metabolic disorders.

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