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Transmission Electron Micrographs of control and Cpt2 AL/L BAT. TEM of BAT from 16-week old Cpt2 AÀ/À and Cpt2 lox/lox mice. Scale bars, 2 um and 500 nm, respectively. White arrowheads pointing to dysmorphic mitochondria. Black arrowheads pointing to fibrin deposition. Lipid Droplet (LD), Red Blood Cell (RBC).
Source publication
Objective:
To determine the role of fatty acid oxidation on the cellular, molecular, and physiologic response of brown adipose tissue to disparate paradigms of chronic thermogenic stimulation.
Methods:
Mice with an adipose-specific loss of Carnitine Palmitoyltransferase 2 (Cpt2A-/-), that lack mitochondrial long chain fatty acid β-oxidation, wer...
Contexts in source publication
Context 1
... on the substantial changes in mitochondrial protein abun- dance, we were surprised that many mitochondria of Cpt2 AÀ/À BAT exhibited normal morphology with abundant cristae. However, Cpt2 AÀ/À BAT did exhibit evidence of dysmorphic mitochondria (Figure 8 white arrowheads) and significant cellular and subcellular heterogeneity. Strikingly, Cpt2 AÀ/À BAT exhibited abundant fibrin deposition (Figure 8 black arrowheads). ...
Context 2
... Cpt2 AÀ/À BAT did exhibit evidence of dysmorphic mitochondria (Figure 8 white arrowheads) and significant cellular and subcellular heterogeneity. Strikingly, Cpt2 AÀ/À BAT exhibited abundant fibrin deposition (Figure 8 black arrowheads). These data show that Cpt2 AÀ/À mice exhibit structurally normal BAT and mitochondria, interspersed with dysmorphic cells and organelles including large fibrotic areas. ...
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An excess of glucocorticoids leads to the development of obesity in both mice and humans, but the mechanism for this is unknown. Here, we determine the extent to which decreased BAT thermogenic capacity (as a result of glucocorticoid treatment) contributes to the development of obesity. Contrary to previous suggestions, we show that only in mice ho...
Citations
... However, maternal obesity promoted decreased expression of the mitochondrial biogenesis-related genes Ppargc1a and Prdm16, whose protein activities favor fatty acid oxidation [90,91], at P20 OD females compared to P20 CD females, an observation corroborated by the severe adipocyte hypertrophy detected at P20 OD female mice. Since fatty acid oxidation is a key process in establishing and maintaining a thermogenic phenotype in adipocytes [91,92], its impairment in female OD offspring is involved in the failure of spontaneous browning in these animals. ...
... In addition, our data highlight the upregulation of fatty acid transport, actin cytoskeleton reorganization, and response to unfolded protein (UPR) as characteristic hallmarks of progenitor cell progression toward the beige lineage. Prior studies have drawn associations between genes within these pathways and the thermogenic capacity of adipose tissue suggesting the potential for manipulating these pathways to enhance beige adipogenesis 49,50,51,52 . A particularly intriguing observation pertains to the activation of UPR in response to cold exposure. ...
In adult white adipose tissue, cold or β3-adrenoceptor activation promotes the appearance of thermogenic beige adipocytes. Our comprehensive single-cell analysis revealed that these cells arise through the reprogramming of existing adipogenic trajectories, rather than from a single precursor. These trajectories predominantly arise from SM22-expressing vascular mural progenitor cells. Central in this transition is the activation of Adrb3 in mature adipocytes, leading to subsequent upregulation of Adrb1 in primed progenitors. Under thermoneutral conditions, synergistic activation of both Adrb3 and Adrb1 recapitulates the pattern of cold-induced SM22+ cell recruitment. Lipolysis-derived eicosanoids, specifically docosahexaenoic acid (DHA) and arachidonic acid (AA) prime these processes and in vitro, were sufficient to recapitulate progenitor cells priming. Collectively, our findings provide a robust model for cold-induced beige adipogenesis, emphasizing a profound relationship between mature adipocytes and mural cells during cold acclimation, and revealing the metabolic potential of this unique cellular reservoir.
... Long-term nutritional interventions contribute nonpharmacologically to increasing BAT mass and activity, helping in obesity management [12]. In addition, mitochondrial long-chain fatty acid beta-oxidation helps maintain brown adipocyte phenotype during activation and quiescence [13]. ...
... In addition, our data highlight the upregulation of fatty acid transport, actin cytoskeleton reorganization, and response to unfolded protein (UPR) as characteristic hallmarks of progenitor cell progression toward the beige lineage. Prior studies have drawn associations between genes within these pathways and the thermogenic capacity of adipose tissue suggesting the potential for manipulating these pathways to enhance beige adipogenesis 44,45,46,47 . A particularly intriguing observation pertains to the activation of UPR in response to cold exposure. ...
In adult white adipose tissue, cold or β3-adrenoceptor activation promotes the appearance of thermogenic beige adipocytes. Our comprehensive single-cell analysis revealed that these cells arise through the reprogramming of existing adipogenic trajectories, rather than from a single precursor. These trajectories predominantly arise from SM22-expressing vascular mural progenitor cells. Central in this transition is the activation of Adrb3 in mature adipocytes, leading to subsequent upregulation of Adrb1 in primed progenitors. Under thermoneutral conditions, synergistic activation of both Adrb3 and Adrb1 recapitulates the pattern of cold-induced SM22+ cell recruitment. Lipolysis-derived eicosanoids, specifically docosahexaenoic acid (DHA) and arachidonic acid (AA) prime these processes and in vitro, were sufficient to recapitulate progenitor cells priming. Collectively, our findings provide a robust model for cold-induced beige adipogenesis, emphasizing a profound relationship between mature adipocytes and mural cells during cold acclimation, and revealing the metabolic potential of this unique cellular reservoir.
... Mitochondrial fatty acids β-oxidation can produce acetyl coenzyme A (acetyl-CoA), which can be used as the raw material of the tricarboxylic acid cycle (Jeong et al., 2018). β-oxidation is an essential metabolic process in adipose tissue, especially in BAT, which contributes to adipose bioenergetics and is critical for the survival of BAT and the activation of acute thermogenesis during BAT quiescence (Gonzalez-Hurtado et al., 2018). ...
Epidemiological and experimental data have associated exposure to fine particulate matter (PM2.5) with various metabolic dysfunctions and diseases, including overweight and type 2 diabetes. Adipose tissue is an energy pool for storing lipids, a necessary regulator of glucose homeostasis, and an active endocrine organ, playing an essential role in developing various related diseases such as diabetes and obesity. However, the molecular mechanisms underlying PM2.5-impaired functions in adipose tissue have rarely been explored. In this work, metabolomics based on liquid chromatography-mass spectrometry was performed to study the adverse impacts of PM2.5 exposure on brown adipose tissue (BAT) and white adipose tissue (WAT) in the diabetic mouse model. We found the effects of PM2.5 exposure by comparing the different metabolites in both adipose tissues of male db/db mice using real-ambient PM2.5 exposure. The results showed that PM2.5 exposure changed the purine metabolism in mice, especially the dramatic increase of xanthine content in both WAT and BAT. These changes led to significant oxidative stress. Then the results from real-time quantitative polymerase chain reaction showed that PM2.5 exposure could cause the production of inflammatory factors in both adipose tissues. Moreover, the increased reactive oxygen species (ROS) promoted triglyceride accumulation in WAT and inhibited its decomposition, causing increased WAT content in db/db mice. In addition, PM2.5 exposure significantly suppressed thermogenesis and affected energy metabolism in the BAT of male db/db mice, which may deteriorate insulin sensitivity and blood glucose regulation. This research demonstrated the impact of PM2.5 on the adipose tissue of male db/db mice, which may be necessary for public health.
... In young rats 0.5% FF induced only the transcriptional coactivator CITED1, a proposed marker of beige adipocytes (33), but not oxidative metabolismrelated genes. BAT thermogenesis is associated with high energy consumption (34), and β-oxidation is crucial for thermogenic activation as well as for maintenance of the brown adipocyte phenotype (35). PPARα coordinately regulates lipid catabolism and thermogenic gene expression through induction of PGC1α expression (14). ...
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... The thermogenic effect of the CL316243 compound was also confirmed by in vivo studies. When infused in obese mice, this molecule increased EE and reduced body weight in association with increased UCP1-dependent thermogenesis in WAT [74,75]. Notably, CL316243 requires mitochondrial fatty acid oxidation, since obese mice developed a resistance to CL316243-induced thermogenesis when carnitine palmitoyl transferase 2 (CPT2) was genetically abrogated [74]. ...
... When infused in obese mice, this molecule increased EE and reduced body weight in association with increased UCP1-dependent thermogenesis in WAT [74,75]. Notably, CL316243 requires mitochondrial fatty acid oxidation, since obese mice developed a resistance to CL316243-induced thermogenesis when carnitine palmitoyl transferase 2 (CPT2) was genetically abrogated [74]. Furthermore, the efficacy of CL316243 in promoting the activation of brown fat, EE, and weight loss was higher in mice housed at 30 °C compared with mice housed at 22 °C, suggesting that drug efficiency could be also affected by environmental temperature [76]. ...
Background:
Adaptive thermogenesis represents the main mechanism through which the body generates heat in response to external stimuli, a phenomenon that includes shivering and non-shivering thermogenesis. The non-shivering thermogenesis is mainly exploited by adipose tissue characterized by a brown aspect, which specializes in energy dissipation. A decreased amount of brown adipose tissue has been observed in ageing and chronic illnesses such as obesity, a worldwide health problem characterized by dysfunctional adipose tissue expansion and associated cardiometabolic complications. In the last decades, the discovery of a trans-differentiation mechanism ("browning") within white adipose tissue depots, leading to the generation of brown-like cells, allowed to explore new natural and synthetic compounds able to favour this process and thus enhance thermogenesis with the aim of counteracting obesity. Based on recent findings, brown adipose tissue-activating agents could represent another option in addition to appetite inhibitors and inhibitors of nutrient absorption for obesity treatment.
Purpose:
This review investigates the main molecules involved in the physiological (e.g. incretin hormones) and pharmacological (e.g. β3-adrenergic receptors agonists, thyroid receptor agonists, farnesoid X receptor agonists, glucagon-like peptide-1, and glucagon receptor agonists) modulation of adaptive thermogenesis and the signalling mechanisms involved.
... Neither the expression of Ucp1 nor mitochondrial activity was consistently elevated in the BAT of TcMAC21 mice fed chow or HFD. Housing mice at a thermoneutral temperature would suppress BAT activity and beiging in iWAT (Gonzalez-Hurtado et al., 2018), yet TcMAC21 mice housed at thermoneutrality for an extended period (>2 months) retained elevated EE and lean body weight comparable to TcMAC21 mice housed at 22°C. Together, these data argue against BAT being a significant contributor to the thermogenesis seen in TcMAC21 mice. ...
The consequences of aneuploidy have traditionally been studied in cell and animal models in which the extrachromosomal DNA is from the same species. Here, we explore a fundamental question concerning the impact of aneuploidy on systemic metabolism using a non-mosaic transchromosomic mouse model (TcMAC21) carrying a near-complete human chromosome 21. Independent of diets and housing temperatures, TcMAC21 mice consume more calories, are hyperactive and hypermetabolic, remain consistently lean and profoundly insulin sensitive, and have a higher body temperature. The hypermetabolism and elevated thermogenesis are likely due to a combination of increased activity level and sarcolipin overexpression in the skeletal muscle, resulting in futile sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) activity and energy dissipation. Mitochondrial respiration is also markedly increased in skeletal muscle to meet the high ATP demand created by the futile cycle and hyperactivity. This serendipitous discovery provides proof-of-concept that sarcolipin-mediated thermogenesis via uncoupling of the SERCA pump can be harnessed to promote energy expenditure and metabolic health.
... In response to cold stress, the sympathetic nervous system releases norepinephrine to mediate the thermogenic function of brown adipocytes. Norepinephrine and β-adrenergic receptor (βAR) efficiently induce lipolysis and lipography of adipose lipid droplets to promote mitochondrial oxidation and heat production [85][86] . In addition, the βAR-mediated cAMP-PKA-Creb signaling pathway transcriptionally up-regulates the expression of Ucp1, Pgc1a and deiodinase, iodothyronine, type Ⅱ (DIO2), which are essential for cold-induced adipose mitochondrial uncoupling-mediated heat production, mitochondrial biogenesis, and catalyzed T4 to T3 conversion [87][88][89] . ...
Extreme cold environment can threaten human health and life through increasing the risk of myocardial infarction, stroke, frostbite, and hypothermia. Insufficient heat production to maintain core body temperature is a major cause of cold injury. To cope with cold stress, human and other mammals have developed the capacity of cold acclimatization to adapt to such a harsh environment. Adaptive non-shivering thermogenesis is a ubiquitous form of cold acclimatization. This review article systematically summarizes the role of three inducible thermogenic forms, including food intake, circadian rhythms, and cold exposure in mediating non-shivering thermogenesis under cold exposure and presents the potential interventions for minimizing the adverse health consequences of cold temperature.
... Mitochondrial fatty acids β-oxidation can produce acetyl coenzyme A (acetyl-CoA), which can be used as the raw material of the tricarboxylic acid cycle (Jeong et al., 2018). β-oxidation is an essential metabolic process in adipose tissue, especially in BAT, which contributes to adipose bioenergetics and is critical for the survival of BAT and the activation of acute thermogenesis during BAT quiescence (Gonzalez-Hurtado et al., 2018). ...
Epidemiological and experimental data have associated exposure to fine particulate matter (PM2.5) with various metabolic dysfunctions and diseases, including overweight and type 2 diabetes. Adipose tissue is an energy pool for storing lipids, a necessary regulator of glucose homeostasis, and an active endocrine organ, playing an essential role in developing various related diseases such as diabetes and obesity. However, the molecular mechanisms underlying PM2.5-impaired functions in adipose tissue have rarely been explored. In this work, metabolomics based on liquid chromatography-mass spectrometry was performed to study the adverse impacts of PM2.5 exposure on brown adipose tissue (BAT) and white adipose tissue (WAT) in the diabetic mouse model. We found the effects of PM2.5 exposure by comparing the different metabolites in both adipose tissues of male db/db mice using real-ambient PM2.5 exposure. The results showed that PM2.5 exposure changed the purine metabolism in mice, especially the dramatic increase of xanthine content in both WAT and BAT. These changes led to significant oxidative stress. Then the results from real-time quantitative polymerase chain reaction showed that PM2.5 exposure could cause the production of inflammatory factors in both adipose tissues. Moreover, the increased reactive oxygen species (ROS) promoted triglyceride accumulation in WAT and inhibited its decomposition, causing increased WAT content in db/db mice. In addition, PM2.5 exposure significantly suppressed thermogenesis and affected energy metabolism in the BAT of male db/db mice, which may deteriorate insulin sensitivity and blood glucose regulation. This research demonstrated the impact of PM2.5 on the adipose tissue of male db/db mice, which may be necessary for public health.
