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Cell Feb 2022Adipose tissue, colloquially known as "fat," is an extraordinarily flexible and heterogeneous organ. While historically viewed as a passive site for energy storage, we... (Review)
Review
Adipose tissue, colloquially known as "fat," is an extraordinarily flexible and heterogeneous organ. While historically viewed as a passive site for energy storage, we now appreciate that adipose tissue regulates many aspects of whole-body physiology, including food intake, maintenance of energy levels, insulin sensitivity, body temperature, and immune responses. A crucial property of adipose tissue is its high degree of plasticity. Physiologic stimuli induce dramatic alterations in adipose-tissue metabolism, structure, and phenotype to meet the needs of the organism. Limitations to this plasticity cause diminished or aberrant responses to physiologic cues and drive the progression of cardiometabolic disease along with other pathological consequences of obesity.
Topics: Adaptation, Physiological; Adipocytes, White; Adipose Tissue; Animals; Disease; Health; Humans; Thermogenesis
PubMed: 35120662
DOI: 10.1016/j.cell.2021.12.016 -
International Journal of Environmental... Sep 2021Development of obesity is primarily the result of imbalance between energy intake and energy expenditure. Thyroid hormones influence energy expenditure by regulating... (Review)
Review
Development of obesity is primarily the result of imbalance between energy intake and energy expenditure. Thyroid hormones influence energy expenditure by regulating cellular respiration and thermogenesis and by determining resting metabolic rate. Triiodothyronine influences lipid turnover in adipocytes and impacts appetite regulation through the central nervous system, mainly the hypothalamus. Thyroid-stimulating hormone may also influence thermogenesis, suppress appetite and regulate lipid storage through lipolysis and lipogenesis control. Subclinical hypothyroidism may induce changes in basal metabolic rate with subsequent increase in BMI, but obesity can also affect thyroid function via several mechanisms such as lipotoxicity and changes in adipokines and inflammatory cytokine secretion. The present study investigated the complex and mutual relationships between the thyroid axis and adiposity.
Topics: Basal Metabolism; Energy Metabolism; Humans; Obesity; Thermogenesis; Thyroid Gland
PubMed: 34574358
DOI: 10.3390/ijerph18189434 -
Nature Reviews. Molecular Cell Biology Jun 2021Brown and beige adipocytes are mitochondria-enriched cells capable of dissipating energy in the form of heat. These thermogenic fat cells were originally considered to... (Review)
Review
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.
Topics: Adipocytes, Beige; Adipocytes, Brown; Animals; Energy Metabolism; Humans; Lipid Metabolism; Thermogenesis; Uncoupling Protein 1
PubMed: 33758402
DOI: 10.1038/s41580-021-00350-0 -
Cell Reports. Medicine Oct 2021The Scandinavian winter-swimming culture combines brief dips in cold water with hot sauna sessions, with conceivable effects on body temperature. We study thermogenic...
The Scandinavian winter-swimming culture combines brief dips in cold water with hot sauna sessions, with conceivable effects on body temperature. We study thermogenic brown adipose tissue (BAT) in experienced winter-swimming men performing this activity 2-3 times per week. Our data suggest a lower thermal comfort state in the winter swimmers compared with controls, with a lower core temperature and absence of BAT activity. In response to cold, we observe greater increases in cold-induced thermogenesis and supraclavicular skin temperature in the winter swimmers, whereas BAT glucose uptake and muscle activity increase similarly to those of the controls. All subjects demonstrate nocturnal reduction in supraclavicular skin temperature, whereas a distinct peak occurs at 4:30-5:30 a.m. in the winter swimmers. Our data leverage understanding of BAT in adult human thermoregulation, suggest both heat and cold acclimation in winter swimmers, and propose winter swimming as a potential strategy for increasing energy expenditure.
Topics: Adipose Tissue, Brown; Adult; Circadian Rhythm; Cold Temperature; Hormones; Humans; Magnetic Resonance Imaging; Male; Perception; Positron-Emission Tomography; Seasons; Skin Temperature; Swimming; Thermogenesis; Thermography; Young Adult
PubMed: 34755128
DOI: 10.1016/j.xcrm.2021.100408 -
Cell Metabolism Apr 2022Recent findings have demonstrated that mitochondria can be transferred between cells to control metabolic homeostasis. Although the mitochondria of brown adipocytes...
Recent findings have demonstrated that mitochondria can be transferred between cells to control metabolic homeostasis. Although the mitochondria of brown adipocytes comprise a large component of the cell volume and undergo reorganization to sustain thermogenesis, it remains unclear whether an intercellular mitochondrial transfer occurs in brown adipose tissue (BAT) and regulates adaptive thermogenesis. Herein, we demonstrated that thermogenically stressed brown adipocytes release extracellular vesicles (EVs) that contain oxidatively damaged mitochondrial parts to avoid failure of the thermogenic program. When re-uptaken by parental brown adipocytes, mitochondria-derived EVs reduced peroxisome proliferator-activated receptor-γ signaling and the levels of mitochondrial proteins, including UCP1. Their removal via the phagocytic activity of BAT-resident macrophages is instrumental in preserving BAT physiology. Depletion of macrophages in vivo causes the abnormal accumulation of extracellular mitochondrial vesicles in BAT, impairing the thermogenic response to cold exposure. These findings reveal a homeostatic role of tissue-resident macrophages in the mitochondrial quality control of BAT.
Topics: Adipocytes, Brown; Adipose Tissue, Brown; Macrophages; Mitochondria; Thermogenesis; Uncoupling Protein 1
PubMed: 35305295
DOI: 10.1016/j.cmet.2022.02.016 -
ELife Jan 2022Identification of key regulators of energy homeostasis holds important therapeutic promise for metabolic disorders, such as obesity and diabetes. ACE2 cleaves...
Identification of key regulators of energy homeostasis holds important therapeutic promise for metabolic disorders, such as obesity and diabetes. ACE2 cleaves angiotensin II (Ang II) to generate Ang-(1-7) which acts mainly through the Mas1 receptor. Here, we identify ACE2 pathway as a critical regulator in the maintenance of thermogenesis and energy expenditure. We found that ACE2 is highly expressed in brown adipose tissue (BAT) and that cold stimulation increases ACE2 and Ang-(1-7) levels in BAT and serum. knockout mice () and knockout mice () displayed impaired thermogenesis. Mice transplanted with brown adipose tissue from display metabolic abnormalities consistent with those seen in the and knockout mice. In contrast, impaired thermogenesis of obese diabetic mice and high-fat diet-induced obese mice were ameliorated by overexpression of or continuous infusion of Ang-(1-7). Activation of ACE2 pathway was associated with improvement of metabolic parameters, including blood glucose, lipids, and energy expenditure in multiple animal models. Consistently, ACE2 pathway remarkably enhanced the browning of white adipose tissue. Mechanistically, we showed that ACE2 pathway activated Akt/FoxO1 and PKA pathway, leading to induction of UCP1 and activation of mitochondrial function. Our data propose that adaptive thermogenesis requires regulation of ACE2 pathway and highlight novel potential therapeutic targets for the treatment of metabolic disorders.
Topics: Angiotensin-Converting Enzyme 2; Animals; Energy Metabolism; Male; Mice; Mice, Inbred C57BL; Signal Transduction; Thermogenesis
PubMed: 35014608
DOI: 10.7554/eLife.72266 -
Endocrine Reviews Mar 2023Brown adipose tissue (BAT) displays the unique capacity to generate heat through uncoupled oxidative phosphorylation that makes it a very attractive therapeutic target... (Review)
Review
Brown adipose tissue (BAT) displays the unique capacity to generate heat through uncoupled oxidative phosphorylation that makes it a very attractive therapeutic target for cardiometabolic diseases. Here, we review BAT cellular metabolism, its regulation by the central nervous and endocrine systems and circulating metabolites, the plausible roles of this tissue in human thermoregulation, energy balance, and cardiometabolic disorders, and the current knowledge on its pharmacological stimulation in humans. The current definition and measurement of BAT in human studies relies almost exclusively on BAT glucose uptake from positron emission tomography with 18F-fluorodeoxiglucose, which can be dissociated from BAT thermogenic activity, as for example in insulin-resistant states. The most important energy substrate for BAT thermogenesis is its intracellular fatty acid content mobilized from sympathetic stimulation of intracellular triglyceride lipolysis. This lipolytic BAT response is intertwined with that of white adipose (WAT) and other metabolic tissues, and cannot be independently stimulated with the drugs tested thus far. BAT is an interesting and biologically plausible target that has yet to be fully and selectively activated to increase the body's thermogenic response and shift energy balance. The field of human BAT research is in need of methods able to directly, specifically, and reliably measure BAT thermogenic capacity while also tracking the related thermogenic responses in WAT and other tissues. Until this is achieved, uncertainty will remain about the role played by this fascinating tissue in human cardiometabolic diseases.
Topics: Humans; Adipose Tissue, Brown; Obesity; Thermogenesis; Energy Metabolism; Cardiovascular Diseases
PubMed: 35640259
DOI: 10.1210/endrev/bnac015 -
American Journal of Physiology.... Mar 2021Brown adipose tissue (BAT) has been encouraged as a potential treatment for obesity and comorbidities due to its thermogenic activity capacity and contribution to energy... (Review)
Review
Brown adipose tissue (BAT) has been encouraged as a potential treatment for obesity and comorbidities due to its thermogenic activity capacity and contribution to energy expenditure. Some interventions such as cold and β-adrenergic drugs are able to activate BAT thermogenesis as well as promote differentiation of white adipocytes into brown-like cells (browning), enhancing the thermogenic activity of these cells. In this mini-review, we discuss new mechanisms related to BAT and energy expenditure. In this regard, we will also discuss recent studies that have revealed the existence of important secretory molecules from BAT "batokines" that act in autocrine, paracrine, and endocrine mechanisms, which in turn may explain some of the beneficial roles of BAT on whole body glucose and fat metabolism. Finally, we will discuss new insights related to BAT thermogenesis with an additional focus on the distinct features of BAT metabolism between rodents and humans.
Topics: Adipocytes, White; Adipose Tissue, Brown; Animals; Energy Metabolism; Glucose; Humans; Thermogenesis
PubMed: 33459179
DOI: 10.1152/ajpendo.00310.2020 -
Nature Sep 2022Compelling evidence shows that brown and beige adipose tissue are protective against metabolic diseases. PR domain-containing 16 (PRDM16) is a dominant activator of the...
Compelling evidence shows that brown and beige adipose tissue are protective against metabolic diseases. PR domain-containing 16 (PRDM16) is a dominant activator of the biogenesis of beige adipocytes by forming a complex with transcriptional and epigenetic factors and is therefore an attractive target for improving metabolic health. However, a lack of knowledge surrounding the regulation of PRDM16 protein expression hampered us from selectively targeting this transcriptional pathway. Here we identify CUL2-APPBP2 as the ubiquitin E3 ligase that determines PRDM16 protein stability by catalysing its polyubiquitination. Inhibition of CUL2-APPBP2 sufficiently extended the half-life of PRDM16 protein and promoted beige adipocyte biogenesis. By contrast, elevated CUL2-APPBP2 expression was found in aged adipose tissues and repressed adipocyte thermogenesis by degrading PRDM16 protein. Importantly, extended PRDM16 protein stability by adipocyte-specific deletion of CUL2-APPBP2 counteracted diet-induced obesity, glucose intolerance, insulin resistance and dyslipidaemia in mice. These results offer a cell-autonomous route to selectively activate the PRDM16 pathway in adipose tissues.
Topics: Animals; Mice; Adipocytes, Beige; Adipose Tissue, Beige; Adipose Tissue, Brown; Cullin Proteins; DNA-Binding Proteins; Dyslipidemias; Glucose Intolerance; Insulin Resistance; Obesity; Protein Stability; Thermogenesis; Transcription Factors; Ubiquitination
PubMed: 35978186
DOI: 10.1038/s41586-022-05067-4 -
Cell Jan 2023Public health studies indicate that artificial light is a high-risk factor for metabolic disorders. However, the neural mechanism underlying metabolic modulation by...
Public health studies indicate that artificial light is a high-risk factor for metabolic disorders. However, the neural mechanism underlying metabolic modulation by light remains elusive. Here, we found that light can acutely decrease glucose tolerance (GT) in mice by activation of intrinsically photosensitive retinal ganglion cells (ipRGCs) innervating the hypothalamic supraoptic nucleus (SON). Vasopressin neurons in the SON project to the paraventricular nucleus, then to the GABAergic neurons in the solitary tract nucleus, and eventually to brown adipose tissue (BAT). Light activation of this neural circuit directly blocks adaptive thermogenesis in BAT, thereby decreasing GT. In humans, light also modulates GT at the temperature where BAT is active. Thus, our work unveils a retina-SON-BAT axis that mediates the effect of light on glucose metabolism, which may explain the connection between artificial light and metabolic dysregulation, suggesting a potential prevention and treatment strategy for managing glucose metabolic disorders.
Topics: Mice; Animals; Humans; Adipose Tissue, Brown; Hypothalamus; Thermogenesis; Retina; Retinal Ganglion Cells; Glucose
PubMed: 36669474
DOI: 10.1016/j.cell.2022.12.024