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Nature Communications Aug 2023Thermal homeostasis is vital for mammals and is controlled by brain neurocircuits. Yet, the neural pathways responsible for cold defense regulation are still unclear....
Thermal homeostasis is vital for mammals and is controlled by brain neurocircuits. Yet, the neural pathways responsible for cold defense regulation are still unclear. Here, we found that a pathway from the lateral parabrachial nucleus (LPB) to the dorsomedial hypothalamus (DMH), which runs parallel to the canonical LPB to preoptic area (POA) pathway, is also crucial for cold defense. Together, these pathways make an equivalent and cumulative contribution, forming a parallel circuit. Specifically, activation of the LPB → DMH pathway induced strong cold-defense responses, including increases in thermogenesis of brown adipose tissue (BAT), muscle shivering, heart rate, and locomotion. Further, we identified somatostatin neurons in the LPB that target DMH to promote BAT thermogenesis. Therefore, we reveal a parallel circuit governing cold defense in mice, which enables resilience to hypothermia and provides a scalable and robust network in heat production, reshaping our understanding of neural circuit regulation of homeostatic behaviors.
Topics: Mice; Animals; Thermogenesis; Preoptic Area; Neural Pathways; Homeostasis; Hypothermia; Adipose Tissue, Brown; Cold Temperature; Mammals
PubMed: 37582782
DOI: 10.1038/s41467-023-40504-6 -
Nature Metabolism Nov 2022Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis. Aside from cAMP signalling downstream of β-adrenergic receptor activation, how NA promotes...
Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis. Aside from cAMP signalling downstream of β-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated α-adrenergic receptor (AR) and β-AR signalling induces the expression of thermogenic genes of the futile creatine cycle, and that early B cell factors, oestrogen-related receptors and PGC1α are required for this response in vivo. NA triggers physical and functional coupling between the α-AR subtype (ADRA1A) and Gα to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase B and tissue-non-specific alkaline phosphatase. Combined Gα and Gα signalling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and creatine kinase B is required for this effect. Thus, the ADRA1A-Gα-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.
Topics: Creatine; Thermogenesis; Adipocytes; Energy Metabolism; Creatine Kinase
PubMed: 36344764
DOI: 10.1038/s42255-022-00667-w -
PLoS Biology Jan 2018Mitochondria generate most of the heat in endotherms. Given some impedance of heat transfer across protein-rich bioenergetic membranes, mitochondria must operate at a...
Mitochondria generate most of the heat in endotherms. Given some impedance of heat transfer across protein-rich bioenergetic membranes, mitochondria must operate at a higher temperature than body temperature in mammals and birds. But exactly how much hotter has been controversial, with physical calculations suggesting that maximal heat gradients across cells could not be greater than 10(-5) K. Using the thermosensitive mitochondrial-targeted fluorescent dye Mito Thermo Yellow (MTY), Chrétien and colleagues suggest that mitochondria are optimised to nearly 50 °C, 10 °C hotter than body temperature. This extreme value questions what temperature really means in confined far-from-equilibrium systems but encourages a reconsideration of thermal biology.
Topics: Animals; Energy Metabolism; Fluorescent Dyes; Hot Temperature; Humans; Membrane Proteins; Mitochondria; Temperature; Thermogenesis; Xanthenes
PubMed: 29370159
DOI: 10.1371/journal.pbio.2005113 -
Nature Metabolism Jul 2023Adaptive thermogenesis by brown adipose tissue (BAT) dissipates calories as heat, making it an attractive anti-obesity target. Yet how BAT contributes to circulating...
Adaptive thermogenesis by brown adipose tissue (BAT) dissipates calories as heat, making it an attractive anti-obesity target. Yet how BAT contributes to circulating metabolite exchange remains unclear. Here, we quantified metabolite exchange in BAT and skeletal muscle by arteriovenous metabolomics during cold exposure in fed male mice. This identified unexpected metabolites consumed, released and shared between organs. Quantitative analysis of tissue fluxes showed that glucose and lactate provide ~85% of carbon for adaptive thermogenesis and that cold and CL316,243 trigger markedly divergent fuel utilization profiles. In cold adaptation, BAT also dramatically increases nitrogen uptake by net consuming amino acids, except glutamine. Isotope tracing and functional studies suggest glutamine catabolism concurrent with synthesis via glutamine synthetase, which avoids ammonia buildup and boosts fuel oxidation. These data underscore the ability of BAT to function as a glucose and amino acid sink and provide a quantitative and comprehensive landscape of BAT fuel utilization to guide translational studies.
Topics: Male; Animals; Mice; Adipose Tissue, Brown; Glutamine; Glucose; Thermogenesis; Muscle, Skeletal
PubMed: 37337122
DOI: 10.1038/s42255-023-00825-8 -
Journal of Applied Physiology... May 2021The pathogenesis of metabolic diseases such as obesity and type 2 diabetes are characterized by a progressive dysregulation in energy partitioning, often leading to...
The pathogenesis of metabolic diseases such as obesity and type 2 diabetes are characterized by a progressive dysregulation in energy partitioning, often leading to end-organ complications. One emerging approach proposed to target this metabolic dysregulation is the application of mild cold exposure. In healthy individuals, cold exposure can increase energy expenditure and whole body glucose and fatty acid utilization. Repeated exposures can lower fasting glucose and insulin levels and improve dietary fatty acid handling, even in healthy individuals. Despite its apparent therapeutic potential, little is known regarding the effects of cold exposure in populations for which this stimulation could benefit the most. The few studies available have shown that both acute and repeated exposures to the cold can improve insulin sensitivity and reduce fasting glycemia in individuals with type 2 diabetes. However, critical gaps remain in understanding the prolonged effects of repeated cold exposures on glucose regulation and whole body insulin sensitivity in individuals with metabolic syndrome. Much of the metabolic benefits appear to be attributable to the recruitment of shivering skeletal muscles. However, further work is required to determine whether the broader recruitment of skeletal muscles observed during cold exposure can confer metabolic benefits that surpass what has been historically observed from endurance exercise. In addition, although cold exposure offers unique cardiovascular responses for a physiological stimulus that increases energy expenditure, further work is required to determine how acute and repeated cold exposure can impact cardiovascular responses and myocardial function across a broader scope of individuals.
Topics: Cold Temperature; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Insulin Resistance; Obesity; Shivering; Thermogenesis
PubMed: 33764169
DOI: 10.1152/japplphysiol.00934.2020 -
Annual Review of Physiology Feb 2021Adipose tissue depots in distinct anatomical locations mediate key aspects of metabolism, including energy storage, nutrient release, and thermogenesis. Although... (Review)
Review
Adipose tissue depots in distinct anatomical locations mediate key aspects of metabolism, including energy storage, nutrient release, and thermogenesis. Although adipocytes make up more than 90% of adipose tissue volume, they represent less than 50% of its cellular content. Here, I review recent advances in genetic lineage tracing and transcriptomics that reveal the identities of the heterogeneous cell populations constituting mouse and human adipose tissues. In addition to mature adipocytes and their progenitors, these include endothelial and various immune cell types that together orchestrate adipose tissue development and functions. One salient finding is the identification of progenitor subtypes that can modulate adipogenic capacity through paracrine mechanisms. Another is the description of fate trajectories of monocyte/macrophages, which can respond maladaptively to nutritional and thermogenic stimuli, leading to metabolic disease. These studies have generated an extraordinary source of publicly available data that can be leveraged to explore commonalities and differences among experimental models, providing new insights into adipose tissues and their role in metabolic disease.
Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Humans; Thermogenesis
PubMed: 33566675
DOI: 10.1146/annurev-physiol-031620-095446 -
Molecular Metabolism Jul 2019Thermogenic adipocytes reorganize their metabolism during cold exposure. Metabolic reprogramming requires readily available bioenergetics substrates, such as glucose and... (Review)
Review
BACKGROUND
Thermogenic adipocytes reorganize their metabolism during cold exposure. Metabolic reprogramming requires readily available bioenergetics substrates, such as glucose and fatty acids, to increase mitochondrial respiration and produce heat via the uncoupling protein 1 (UCP1). This condition generates a finely-tuned production of mitochondrial reactive oxygen species (ROS) that support non-shivering thermogenesis.
SCOPE OF REVIEW
Herein, the findings underlining the mechanisms that regulate ROS production and control of the adaptive responses tuning thermogenesis in adipocytes are described. Furthermore, this review describes the metabolic responses to substrate availability and the consequence of mitochondrial failure to switch fuel oxidation in response to changes in nutrient availability. A framework to control mitochondrial ROS threshold to maximize non-shivering thermogenesis in adipocytes is provided.
MAJOR CONCLUSIONS
Thermogenesis synchronizes fuel oxidation with an acute and transient increase of mitochondrial ROS that promotes the activation of redox-sensitive thermogenic signaling cascade and UCP1. However, an overload of substrate flux to mitochondria causes a massive and damaging mitochondrial ROS production that affects mitochondrial flexibility. Finding novel thermogenic redox targets and manipulating ROS concentration in adipocytes appears to be a promising avenue of research for improving thermogenesis and counteracting metabolic diseases.
Topics: Adipocytes; Diabetes Mellitus, Type 2; Mitochondria; Obesity; Oxidation-Reduction; Reactive Oxygen Species; Signal Transduction; Thermogenesis; Uncoupling Protein 1
PubMed: 31005563
DOI: 10.1016/j.molmet.2019.04.002 -
Archives of Biochemistry and Biophysics Nov 2022Selenium (Se) is involved in energy metabolism in the liver, white adipose tissue, and skeletal muscle, and may also play a role in thermogenic adipocytes, i.e. brown... (Review)
Review
Selenium (Se) is involved in energy metabolism in the liver, white adipose tissue, and skeletal muscle, and may also play a role in thermogenic adipocytes, i.e. brown and beige adipocytes. Thereby this micronutrient is a key nutritional target to aid in combating obesity and metabolic diseases. In thermogenic adipocytes, particularly in brown adipose tissue (BAT), the selenoprotein type 2 iodothyronine deiodinase (DIO2) is essential for the activation of adaptive thermogenesis. Recent evidence has suggested that additional selenoproteins may also be participating in this process, and a role for Se itself through its metabolic pathways is also envisioned. In this review, we discuss the recognized effects and the knowledge gaps in the involvement of Se metabolism and selenoproteins in the mechanisms of adaptive thermogenesis in thermogenic (brown and beige) adipocytes.
Topics: Selenium; Thermogenesis; Adipose Tissue, Brown; Adipocytes; Energy Metabolism; Selenoproteins
PubMed: 36265651
DOI: 10.1016/j.abb.2022.109445 -
Adipocyte Dec 2023Brown adipocytes were proposed to reverse metabolic conditions such as obesity and diabetes, which make them potential for therapeutic applications. Brown adipocytes and... (Review)
Review
Brown adipocytes were proposed to reverse metabolic conditions such as obesity and diabetes, which make them potential for therapeutic applications. Brown adipocytes and browning process are capable of thermogenesis, the uncoupling metabolism which allows them to promote balanced energy expenditure, a fundamental mechanism for improving metabolic disorders. Thermogenesis process is not only performed by the thermogenin UCPs within the mitochondria, but instead, is globally regulated within brown and browning adipose tissues, which induces signalling molecules that can be sent to nearby and distant tissues to generate systemic effects on metabolism. This review highlights thermogenesis and describes the crosstalk between different organelles within browning and brown adipocytes, as well as their interorgan axes to regulate whole body metabolism. Finally, browning and thermogenesis activation will also be discussed in terms of physiological conditions, in which, we propose that thermogenesis and functional activities of brown adipocytes should be considered individually in future clinical application.
Topics: Adipocytes, Brown; Mitochondria; Energy Metabolism; Adipose Tissue; Thermogenesis
PubMed: 37488770
DOI: 10.1080/21623945.2023.2237164 -
Cell Mar 2022Maintenance of body temperature is intimately tied to energy expenditure and body weight regulation. In this issue of Cell, Li, Wang, et al. discovered that localized...
Maintenance of body temperature is intimately tied to energy expenditure and body weight regulation. In this issue of Cell, Li, Wang, et al. discovered that localized hyperthermia induces the thermogenic program to increase energy expenditure and decrease body weight in mice and humans.
Topics: Adipocytes; Animals; Body Weight; Energy Metabolism; Mice; Thermogenesis
PubMed: 35303425
DOI: 10.1016/j.cell.2022.02.024