Thermogenic Adipocytes Research Articles

Cold-responsive adipocyte progenitors couple adrenergic signaling to immune cell activation to promote beige adipocyte accrual.

The full array of cold-responsive cell types within white adipose tissue that drive thermogenic beige adipocyte biogenesis remains undefined. We demonstrate that acute cold challenge elicits striking transcriptomic changes specifically within DPP4+ PDGFRβ+ adipocyte precursor cells, including a β-adrenergic receptor CREB-mediated induction in the expression of the prothermogenic cytokine, Il33 Doxycycline-inducible deletion of Il33 in PDGFRβ+ cells at the onset of cold exposure attenuates ILC2 accumulation and beige adipocyte accrual. These studies highlight the multifaceted roles for adipocyte progenitors and the ability of select mesenchymal subpopulations to relay neuronal signals to tissue-resident immune cells in order to regulate tissue plasticity.

A Role of Stress Sensor Nrf2 in Stimulating Thermogenesis and Energy Expenditure.

During chronic cold stress, thermogenic adipocytes generate heat through uncoupling of mitochondrial respiration from ATP synthesis. Recent discovery of various dietary phytochemicals, endogenous metabolites, synthetic compounds, and their molecular targets for stimulating thermogenesis has provided promising strategies to treat or prevent obesity and its associated metabolic diseases. Nuclear factor E2 p45-related factor 2 (Nrf2) is a stress response protein that plays an important role in obesity and metabolisms. However, both Nrf2 activation and Nrf2 inhibition can suppress obesity and metabolic diseases. Here, we summarized and discussed conflicting findings of Nrf2 activities accounting for part of the variance in thermogenesis and energy metabolism. We also discussed the utility of Nrf2-activating mechanisms for their potential applications in stimulating energy expenditure to prevent obesity and improve metabolic deficits.

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

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.

Impact of thermogenesis induced by chronic β3-adrenergic receptor agonist treatment on inflammatory and infectious response during bacteremia in mice.

White adipocytes store energy differently than brown and brite adipocytes which dissipate energy under the form of heat. Studies have shown that adipocytes are able to respond to bacteria thanks to the presence of Toll-like receptors at their surface. Despite this, little is known about the involvement of each class of adipocytes in the infectious response. We treated mice for one week with a β3-adrenergic receptor agonist to induce activation of brown adipose tissue and brite adipocytes within white adipose tissue. Mice were then injected intraperitoneally with E. coli to generate acute infection. The metabolic, infectious and inflammatory parameters of the mice were analysed during 48 hours after infection. Our results shown that in response to bacteria, thermogenic activity promoted a discrete and local anti-inflammatory environment in white adipose tissue characterized by the increase of the IL-1RA secretion. More generally, activation of brown and brite adipocytes did not modify the host response to infection including no additive effect with fever and an equivalent bacteria clearance and inflammatory response. In conclusion, these results suggest an IL-1RA-mediated immunomodulatory activity of thermogenic adipocytes in response to acute bacterial infection and open a way to characterize their effect along more chronic infection as septicaemia.

Adipocyte Heterogeneity Underlying Adipose Tissue Functions.

Adipose tissue distribution in the human body is highly heterogeneous, and the relative mass of different depots is differentially associated with metabolic disease risk. Distinct functions of adipose depots are mediated by their content of specialized adipocyte subtypes, best exemplified by thermogenic adipocytes found in specific depots. Single-cell transcriptome profiling has been used to define the cellular composition of many tissues and organs, but the large size, buoyancy, and fragility of adipocytes have rendered it challenging to apply these techniques to understand the full complexity of adipocyte subtypes in different depots. Discussed here are strategies that have been recently developed for investigating adipocyte heterogeneity, including single-cell RNA-sequencing profiling of the stromal vascular fraction to identify diverse adipocyte progenitors, and single-nuclei profiling to characterize mature adipocytes. These efforts are yielding a more complete characterization of adipocyte subtypes in different depots, insights into the mechanisms of their development, and perturbations associated with different physiological states such as obesity. A better understanding of the adipocyte subtypes that compose different depots will help explain metabolic disease phenotypes associated with adipose tissue distribution and suggest new strategies for improving metabolic health.

Therapeutic Perspectives of Thermogenic Adipocytes in Obesity and Related Complications.

There is a rapidly increasing prevalence of obesity and related metabolic disorders such as type 2 diabetes worldwide. White adipose tissue (WAT) stores excess energy, whereas brown and beige adipose tissues consume energy to generate heat in the process of thermogenesis. Adaptive thermogenesis occurs in response to environmental cues as a means of generating heat by dissipating stored chemical energy. Due to its cumulative nature, very small differences in energy expenditure from adaptive thermogenesis can have a significant impact on systemic metabolism over time. Targeting brown adipose tissue (BAT) activation and converting WAT to beige fat as a method to increase energy expenditure is one of the promising strategies to combat obesity. In this review, we discuss the activation of the thermogenic process in response to physiological conditions. We highlight recent advances in harnessing the therapeutic potential of thermogenic adipocytes by genetic, pharmacological and cell-based approaches in the treatment of obesity and metabolic disorders in mice and the human.

GPR3 sets brown fat on fire

Activation of thermogenic adipocytes, a process canonically driven by norepinephrine through β-adrenergic receptors, presents an appealing therapeutic approach to combat obesity. Recent work by Sveidahl Johansen et al., 2021 published in Cell has identified a noncanonical mechanism of brown adipocyte activation, in which lipolysis transcriptionally drives the constitutive activation of the Gs protein-coupled receptor, GPR3, to induce thermogenesis.

Intercellular and inter-organ crosstalk in browning of white adipose tissue: molecular mechanism and therapeutic complications.

Adipose tissue (AT) is highly plastic and heterogeneous in response to environmental and nutritional changes. The development of heat-dissipating beige adipocytes in white AT (WAT) through a process known as browning (or beiging) has garnered much attention as a promising therapeutic strategy for obesity and its related metabolic complications. This is due to its inducibility in response to thermogenic stimulation and its association with improved metabolic health. WAT consists of adipocytes, nerves, vascular endothelial cells, various types of immune cells, adipocyte progenitor cells, and fibroblasts. These cells contribute to the formation of beige adipocytes through the release of protein factors that significantly influence browning capacity. In addition, inter-organ crosstalk is also important for beige adipocyte biogenesis. Here, we summarize recent findings on fat depot-specific differences, secretory factors participating in intercellular and inter-organ communications that regulate the recruitment of thermogenic beige adipocytes, as well as challenges in targeting beige adipocytes as a potential anti-obese therapy.

Brown Fat as a Regulator of Systemic Metabolism beyond Thermogenesis.

Brown adipose tissue (BAT) is a specialized tissue for nonshivering thermogenesis to dissipate energy as heat. Although BAT research has long been limited mostly in small rodents, the rediscovery of metabolically active BAT in adult humans has dramatically promoted the translational studies on BAT in health and diseases. Moreover, several remarkable advancements have been made in brown fat biology over the past decade: The molecular and functional analyses of inducible thermogenic adipocytes (socalled beige adipocytes) arising from a developmentally different lineage from classical brown adipocytes have been accelerated. In addition to a well-established thermogenic activity of uncoupling protein 1 (UCP1), several alternative thermogenic mechanisms have been discovered, particularly in beige adipocytes. It has become clear that BAT influences other peripheral tissues and controls their functions and systemic homeostasis of energy and metabolic substrates, suggesting BAT as a metabolic regulator, other than for thermogenesis. This notion is supported by discovering that various paracrine and endocrine factors are secreted from BAT. We review the current understanding of BAT pathophysiology, particularly focusing on its role as a metabolic regulator in small rodents and also in humans.

Plasticity and heterogeneity of thermogenic adipose tissue.

The perception of adipose tissue, both in the scientific community and in the general population, has changed dramatically in the past 20 years. While adipose tissue was thought for a long time to be a rather simple lipid storage entity, it is now recognized as a highly heterogeneous organ and a critical regulator of systemic metabolism, composed of many different subtypes of cells, with important endocrine functions. Additionally, adipose tissue is nowadays recognized to contribute to energy turnover, due to the presence of specialized thermogenic adipocytes, which can be found in many adipose depots. This review discusses the unprecedented insights that we have gained into the heterogeneity of thermogenic adipocytes and their respective precursors due to the technical developments in single-cell and nucleus technologies. These methodological advances have increased our understanding of how adipose tissue catabolic function is influenced by developmental and intercellular communication events.

LncRNA Ctcflos orchestrates transcription and alternative splicing in thermogenic adipogenesis.

The recruitment of thermogenic brite adipocytes within white adipose tissue attenuates obesity and metabolic comorbidities, arousing interest in understanding the underlying regulatory mechanisms. The molecular network of brite adipogenesis, however, remains largely unresolved. In this light, long noncoding RNAs (lncRNAs) emerged as a versatile class of modulators that control many steps within the differentiation machinery. Leveraging the naturally varying propensities of different inbred mouse strains for white adipose tissue browning, we identify the nuclear lncRNA Ctcflos as a pivotal orchestrator of thermogenic gene expression during brite adipocyte differentiation. Mechanistically, Ctcflos acts as a pleiotropic regulator, being essential for the transcriptional recruitment of the early core thermogenic regulatory program and the modulation of alternative splicing to drive brite adipogenesis. This is showcased by Ctcflos‐regulated gene transcription and splicing of the key browning factor Prdm16 toward the isoform that is specific for the thermogenic gene program. Conclusively, our findings emphasize the mechanistic versatility of lncRNAs acting at several independent levels of gene expression for effective regulation of key differentiation factors to direct cell fate and function.

Thermogenic Fat: Development, Physiological Function, and Therapeutic Potential.

The concerning worldwide increase of obesity and chronic metabolic diseases, such as T2D, dyslipidemia, and cardiovascular disease, motivates further investigations into preventive and alternative therapeutic approaches. Over the past decade, there has been growing evidence that the formation and activation of thermogenic adipocytes (brown and beige) may serve as therapy to treat obesity and its associated diseases owing to its capacity to increase energy expenditure and to modulate circulating lipids and glucose levels. Thus, understanding the molecular mechanism of brown and beige adipocytes formation and activation will facilitate the development of strategies to combat metabolic disorders. Here, we provide a comprehensive overview of pathways and players involved in the development of brown and beige fat, as well as the role of thermogenic adipocytes in energy homeostasis and metabolism. Furthermore, we discuss the alterations in brown and beige adipose tissue function during obesity and explore the therapeutic potential of thermogenic activation to treat metabolic syndrome.

Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis

SummaryThermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.

Oil does more than light the lamp: The multifaceted role of lipids in thermogenic fat.

Brown and beige adipocytes, or thermogenic fat, were initially thought to be merely a thermogenic organ. However, emerging evidence suggests its multifaceted roles in the regulation of systemic glucose and lipid homeostasis that go beyond enhancing thermogenesis. One of the important functions of thermogenic fat is as a "metabolic sink" for glucose, fatty acids, and amino acids, which profoundly impacts metabolite clearance and oxidation. Importantly, lipids are not only the predominant fuel source used for thermogenesis but are also essential molecules for development, cellular signaling, and structural components. Here, we review the multifaceted role of lipids in thermogenic adipocytes.

Regulation of iron homeostasis to support differentiation and thermogenic function of adipocyte

The development of thermogenic adipocytes concurs with mitochondrial biogenesis, an iron-dependent pathway. Iron regulatory protein (IRP) 1 and 2 are RNA-binding proteins that regulate intracellular iron homeostasis. IRPs bind to the iron-response element (IRE) of their target mRNAs, balancing iron uptake and deposition at the post-transcriptional levels. However, IRP/IRE-dependent of iron regulation in adipocytes is largely unknown. We hypothesized that iron demands are higher in brown/beige adipocytes than white adipocytes to maintain the thermogenic mitochondrial capacity. To test this hypothesis, we investigated the IRP/IRE regulatory system in different depots of adipose tissue. Our results revealed that 1) IRP/IRE interaction was increased in proportional to the thermogenic function of the adipose depot, 2) adipose iron content was increased in adipose tissue browning upon b3-adrenoceptor stimulation, while decreased in thermoneutral conditions, and 3) modulation of iron content was linked with mitochondrial biogenesis. Moreover, the iron requirement was higher in HIB1B brown adipocytes than 3T3-L1 white adipocytes during differentiation. The reduction of the labile iron pool (LIP) suppressed the differentiation of brown/beige adipocytes and mitochondrial biogenesis. Using the 59Fe-Tf, we also demonstrated that thermogenic stimuli triggered cell-autonomous iron uptake and mitochondrial compartmentalization as well as enhanced mitochondrial respiration. Collectively, our work demonstrated that IRP/IRE signaling and subsequent adaptation in iron metabolism is a critical determinant for the thermogenic function of adipocytes.

Regulation of Brown Adipose Tissue and Beige Fat by the Adenosine A2B Receptor 8.5.5

Pandemic obesity and its associated co-morbidities like type 2 diabetes, coronary heart disease or stroke is one of the biggest contemporary health problems and there is an urgent need for novel pharmacological treatment. Brown adipose tissue (BAT) is specialized in dissipating energy in the form of heat by uncoupling ATP synthesis due to its unique uncoupling protein 1 (UCP1). BAT abundance is correlated with leanness in humans and, thereby, BAT is a pharmaceutical target for an anti-obesity therapy. Adenosine is a novel alternative activator of human and brown adipocytes. The enigmatic Gs-protein-coupled adenosine A2B receptor is abundantly expressed in murine BAT. Here, we analyzed the role of the A2B receptor in BAT function in a model of diet-induced obesity. Adipose tissue-specific ablation of A2B reduced BAT energy expenditure (EE) in mice, whereas specific pharmacological stimulation of A2B ameliorated obesity concomitant with improved glucose homeostasis. Additionally, A2B activation promoted browning of inguinal WAT together with a reduced pro-inflammatory phenotype. In humans, high A2B expression correlated with high BAT activity and abundance of thermogenic adipocytes in white fat. Moreover, A2B agonist treatment of primary human brown adipocytes resulted in elevated intracellular cAMP levels and increased oxygen consumption, whereas A2B stimulation of primary human white adipocytes promoted upregulation of thermogenic genes. Taken together, our results propose the adenosine A2B receptor as novel target with great potential to increase EE from BAT/brown adipocytes along with promoting browning of white fat. 8.5.5

Identification of thermogenic adipocyte lineages.

Identification of thermogenic adipocyte lineages.

Vascular smooth muscle-derived Trpv1+ progenitors are a source of cold-induced thermogenic adipocytes.

Brown adipose tissue (BAT) and beige fat function in energy expenditure in part due to their role in thermoregulation, making these tissues attractive targets for treating obesity and metabolic disorders. While prolonged cold exposure promotes de novo recruitment of brown adipocytes, the exact sources of cold-induced thermogenic adipocytes are not completely understood. Here, we identify Trpv1-positive vascular smooth muscle (VSM) cells as previously unidentified brown adipocyte progenitors. Analysis of single-cell RNA sequencing from interscapular brown adipose depots reveals, in addition to the previously-known Pdgfra-expressing mesenchymal progenitors, a previously-unidentified VSM-derived adipocyte progenitor (APC) population, which expresses the temperature-sensitive cation channel, Trpv1. Using flow cytometry and lineage tracing, we demonstrate that the Trpv1-positive VSM-APCs are distinct from the Pdgfra-positive progenitors, and can give rise to thermogenic adipocytes in response to cold. Together, these findings illustrate the landscape of the thermogenic adipose niche at the single cell resolution and identify a new cellular origin for the development of brown and beige adipocytes.

DOT1L Regulates Thermogenic Adipocyte Differentiation and Function via Modulating H3K79 Methylation.

Brown and beige adipocytes are characterized as thermogenic adipocytes and have great potential for treating obesity and associated metabolic diseases. In this article, we identify a conserved mammalian lysine 79 of histone H3 (H3K79) methyltransferase, disruptor of telomeric silencing-1 like (DOT1L), as a new epigenetic regulator that controls thermogenic adipocyte differentiation and function. We show that deletion of DOT1L in thermogenic adipocytes potently protects mice from diet-induced obesity, improves glucose homeostasis, alleviates hepatic steatosis, and facilitates adaptive thermogenesis in vivo. Loss of DOT1L in primary preadipocytes significantly promotes brown and beige adipogenesis and thermogenesis in vitro. Mechanistically, DOT1L epigenetically regulates the brown adipose tissue-selective gene program by modulating H3K79 methylation, in particular H3K79me2 modification. Thus, our study demonstrates that DOT1L exerts an important role in energy homeostasis by regulating thermogenic adipocyte differentiation and function.

The cellular and functional complexity of thermogenic fat.

Brown and beige adipocytes are mitochondria-enriched cells capable of dissipating energy in the form of heat. These thermogenic fat cells were originally considered to function solely in heat generation through the action of the mitochondrial protein uncoupling protein 1 (UCP1). In recent years, significant advances have been made in our understanding of the ontogeny, bioenergetics and physiological functions of thermogenic fat. Distinct subtypes of thermogenic adipocytes have been identified with unique developmental origins, which have been increasingly dissected in cellular and molecular detail. Moreover, several UCP1-independent thermogenic mechanisms have been described, expanding the role of these cells in energy homeostasis. Recent studies have also delineated roles for these cells beyond the regulation of thermogenesis, including as dynamic secretory cells and as a metabolic sink. This Review presents our current understanding of thermogenic adipocytes with an emphasis on their development, biological functions and roles in systemic physiology.