β3-Adrenergic receptors regulate human brown/beige adipocyte lipolysis and thermogenesis

Cero, Cheryl; Lea, Hannah J.; Zhu, Kenneth Y.; Shamsi, Farnaz; Tseng, Yu–Hua; Cypess, Aaron M.

doi:10.1172/jci.insight.139160

Cited by 133 publications

(104 citation statements)

References 90 publications

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“…These results imply that GABRA5 LHA facilitate energy expenditure in HFD mice. Then, we examined the expression of candidate genes which are related to thermogenesis in adipose tissues by qRT-PCR analysis using reference gene as 18S ribosomal RNA (Cannon and Nedergaard, 2004; Cero et al, 2021; Contreras et al ., 2015; Kurylowicz et al, 2015; Orozco-Solis et al, 2016; Whittle et al, 2015). Consistent with the metabolic changes, we found that GABRA5 LHA inhibition led to a significant decrease in interscapular BAT (iBAT) mRNA levels of the uncoupling protein Ucp1 , Cidea and Dio2 , but not Prdm16 , Pgc-1 α (Figure 2O).…”

Section: Resultsmentioning

confidence: 99%

Hypothalamic GABRA5-positive Neurons Control Obesity via Astrocytic GABA

Lee

Koh

et al. 2021

Preprint

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SUMMARYThe lateral hypothalamic area (LHA) regulates food intake and energy expenditure. Although LHA neurons innervate adipose tissues, the identity of neurons that regulate fat is undefined. Here we identify that Gabra5-positive neurons in LHA (GABRA5LHA) polysynaptically project to brown and white adipose tissues in the periphery. GABRA5LHA are a distinct subpopulation of GABAergic neurons and show decreased pacemaker firing in diet-induced obesity (DIO) mouse model. Chemogenetic inhibition of GABRA5LHA suppresses energy expenditure and increases weight gain, whereas gene-silencing of Gabra5 in LHA decreases weight gain. In DIO mouse model, GABRA5LHA are tonically inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by MAOB. Gene-silencing of astrocytic MAOB in LHA reduces weight gain significantly without affecting food intake, which is recapitulated by administration of a MAOB inhibitor, KDS2010. We propose that firing of GABRA5LHA facilitates energy expenditure and selective inhibition of astrocytic GABA is a molecular target for treating obesity.

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Section: Resultsmentioning

confidence: 99%

Hypothalamic GABRA5-positive Neurons Control Obesity via Astrocytic GABA

Lee

Koh

et al. 2021

Preprint

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“…Within this context, the browning of WAT into beige adipose tissue has acquired great interest. Non-shivering thermogenesis of BAT and beige adipose tissue promotes an increase in lipolysis of triglycerides and β-oxidation of FAs, resulting in a decrease of adiposity [ 33 , 34 , 35 ]. Redox signaling, derived from mitochondrial ROS, is involved in the activation of this process [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Endothelial NOX5 Expression Modulates Thermogenesis and Lipolysis in Mice Fed with a High-Fat Diet and 3T3-L1 Adipocytes through an Interleukin-6 Dependent Mechanism

et al. 2021

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Obesity is a global health issue associated with the development of metabolic syndrome, which correlates with insulin resistance, altered lipid homeostasis, and other pathologies. One of the mechanisms involved in the development of these pathologies is the increased production of reactive oxygen species (ROS). One of the main producers of ROS is the family of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, among which NOX5 is the most recently discovered member. The aim of the present work is to describe the effect of endothelial NOX5 expression on neighboring adipose tissue in obesity conditions by using two systems. An in vivo model based on NOX5 conditional knock-in mice fed with a high-fat diet and an in vitro model developed with 3T3-L1 adipocytes cultured with conditioned media of endothelial NOX5-expressing bEnd.3 cells, previously treated with glucose and palmitic acid. Endothelial NOX5 expression promoted the expression and activation of specific markers of thermogenesis and lipolysis in the mesenteric and epididymal fat of those mice fed with a high-fat diet. Additionally, the activation of these processes was derived from an increase in IL-6 production as a result of NOX5 activity. Accordingly, 3T3-L1 adipocytes treated with conditioned media of endothelial NOX5-expressing cells, presented higher expression of thermogenic and lipolytic genes. Moreover, endothelial NOX5-expressing bEnd.3 cells previously treated with glucose and palmitic acid also showed interleukin (IL-6) production. Finally, it seems that the increase in IL-6 stimulated the activation of markers of thermogenesis and lipolysis through phosphorylation of STAT3 and AMPK, respectively. In conclusion, in response to obesogenic conditions, endothelial NOX5 activity could promote thermogenesis and lipolysis in the adipose tissue by regulating IL-6 production.

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“…Facultative mechanisms utilize the effector pathways that are poised to promote rapid activation of thermogenesis upon demand, whereas adaptive processes involve the induction of thermogenic gene expression and adipogenesis 2,11,12 . In this regard, b-adrenergic receptor (bAR) signaling has received the most attention [13][14][15] . The bAR cascade signals through Ga s to stimulate the cyclic AMP (cAMP)-dependent pathway to induce macronutrient oxidation and thermogenesis [16][17][18][19][20] .…”

Section: Main Textmentioning

confidence: 99%

“…The a-adrenergic receptor, Adra1a, is enriched in BAT Since much of adipocyte thermogenesis is regulated by the sympathetic nervous system through GPCR signaling in brown adipocytes 13,14,22 , we analyzed ribosomal pro ling data 23 to score GPCR mRNA expression based on two properties: (1) mRNA enrichment in brown adipose tissue (BAT) and (2) mRNA abundance in BAT (10% most abundant GPCRs). Four genes (Adra1a, Adrb1, Ptger1 and Cxcr7) ful lled these criteria (Extended Data Fig.…”

Section: Main Textmentioning

confidence: 99%

Combined α- and β-adrenergic receptor activation triggers thermogenesis by the futile creatine cycle

Kazak

Rahbani

Scholtes

et al. 2022

Preprint

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Noradrenaline is the primary physiological regulator of adipocyte thermogenesis in response to decreased environmental temperature1. However, the molecular factors and effector pathways that lie downstream of noradrenaline-stimulated thermogenesis are still not fully understood but are purportedly driven by cAMP downstream of β-adrenergic receptor (βAR) activation. Furthermore, while the transcriptional mechanisms regulating Ucp1 are well-characterized2, the transcriptional regulation of UCP1-independent thermogenesis is largely unknown. Here, we show that brown adipose tissue (BAT) is primed to respond to environmental cold by triggering coordinated α-adrenergic receptor (αAR) and βAR signaling to induce the expression of thermogenic genes of the futile creatine cycle3,4. Using fat-specific loss-of-function models, we reveal that EBFs, ERRs, and PGC1α are required for the cold-stimulated transcriptional induction of the futile creatine cycle in vivo. Through the application of chemogenetics, we demonstrate that combined fat-selective Gαs (activated by βARs) and Gαq (activated by αARs) signaling elevates whole-body energy expenditure to a greater extent than either signaling pathway alone in a manner that is dependent on the key effector protein of the futile creatine cycle, CKB3. Moreover, genetic and pharmacological studies reveal that CKB is necessary for nearly all of the α1AR-stimulated component of brown adipocyte-intrinsic respiration and is thus critical for the full activation of noradrenaline-stimulated thermogenesis. Thus, the futile creatine cycle is integrated into facultative and adaptive thermogenesis through coordinated α1AR and β3AR signaling.

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β3-Adrenergic receptors regulate human brown/beige adipocyte lipolysis and thermogenesis

Cited by 133 publications

References 90 publications

Hypothalamic GABRA5-positive Neurons Control Obesity via Astrocytic GABA

Hypothalamic GABRA5-positive Neurons Control Obesity via Astrocytic GABA

Endothelial NOX5 Expression Modulates Thermogenesis and Lipolysis in Mice Fed with a High-Fat Diet and 3T3-L1 Adipocytes through an Interleukin-6 Dependent Mechanism

Combined α- and β-adrenergic receptor activation triggers thermogenesis by the futile creatine cycle

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