Upregulation of AMPK during cold exposure occurs via distinct mechanisms in brown and white adipose tissue of the mouse

The effects of cold exposure (48 h at 4 degrees C) and insulin injection (0.5 U/kg iv) on the rates of net 2-[3H]deoxyglucose uptake (Ki) in peripheral tissues were investigated in warm-acclimated rats (25 degrees C). Cold exposure and insulin treatment independently increased Ki values in skeletal muscles (soleus, extensor digitorum longus, and vastus lateralis), heart, white adipose tissue (subcutaneous, gonadal, and retroperitoneal), and brown adipose tissue (P less than 0.01). The effects of cold exposure were particularly evident in brown adipose tissue where the Ki increased greater than 100 times. When the two treatments were combined (insulin injection in cold-exposed rats), it was found that cold exposure synergistically enhanced the maximal insulin responses for glucose uptake in brown adipose tissue, all white adipose tissue depots, and skeletal muscles investigated. The results indicate that cold exposure induces an "insulin-like" effect on Ki that does not appear to be specifically associated with shivering thermogenesis in skeletal muscles, because that effect was observed in all insulin-sensitive tissues. The data also demonstrate that cold exposure significantly potentiates the maximal insulin responses for glucose uptake in the same tissues. This potentialization may result from an enhanced responsiveness of peripheral tissues to insulin, possibly occurring at metabolic steps lying beyond the insulin receptor and an increased tissue blood flow augmenting glucose and insulin availability and thereby amplifying glucose uptake.

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Single cell atlas of beige remodeling of white adipose tissue reveals a myeloid to lymphoid shift during cold exposure compared to beta 3 adrenergic stimulation

10.1101/2020.05.30.125146 ◽

2020 ◽

Author(s):

Nabil Rabhi ◽

Anna C. Belkina ◽

Kathleen Desevin ◽

Briana Noel Cortez ◽

Stephen R. Farmer

Keyword(s):

Adipose Tissue ◽

Single Cell ◽

White Adipose Tissue ◽

Cold Exposure ◽

Immune Cells ◽

Drug Targets ◽

Stromal Vascular Fraction ◽

Adrenergic Stimulation ◽

Cellular Dynamics ◽

Metabolic Complications

SUMMARYWhite adipose tissue (WAT) is a dynamic tissue, which responds to environmental stimuli and dietary cues by changing its morphology and metabolic capacity. The ability of WAT to undergo a beige remodeling has become an appealing strategy to combat obesity and its related metabolic complications. Within the cell mixture that constitutes the stromal vascular fraction (SVF), WAT beiging is initiated through expansion and differentiation of adipocytes progenitor cells, however, the extent of the SVF cellular changes is still poorly understood. Additionally, direct beta 3 adrenergic receptor (Adrb3) stimulation has been extensively used to mimic physiological cold- induced beiging, yet it is still unknown whether Adrb3 activation induces the same WAT remodeling as cold exposure. Here, by using single cell RNA sequencing, we provide a comprehensive atlas of the cellular dynamics during beige remodeling within white adipose tissue. We reveal drastic changes both in the overall cellular composition and transcriptional states of individual cell subtypes between Adrb3- and cold-induced beiging. Moreover, we demonstrate that cold exposure induces a myeloid to lymphoid shift of the immune compartment compared to Adrb3 activation. Further analysis, showed that Adrb3 stimulation leads to activation of the interferon/Stat1 pathways favoring infiltration of myeloid immune cells, while repression of this pathway by cold promotes lymphoid immune cells recruitment. These findings provide new insight into the cellular dynamics during WAT beige remodeling and could ultimately lead to novel strategies to identify translationally-relevant drug targets to counteract obesity and T2D.

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The effects of exercise and cold exposure on mitochondrial biogenesis in skeletal muscle and white adipose tissue

The Journal of Exercise Nutrition and Biochemistry ◽

10.20463/jenb.2017.0020 ◽

2017 ◽

Vol 21 (2) ◽

pp. 39-47 ◽

Cited By ~ 11

Author(s):

Nana Chung ◽

Jonghoon Park ◽

Kiwon Lim

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Mitochondrial Biogenesis ◽

Cold Exposure

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CD137 negatively affects “browning” of white adipose tissue during cold exposure

Journal of Biological Chemistry ◽

10.1074/jbc.ac119.011795 ◽

2020 ◽

Vol 295 (7) ◽

pp. 2034-2042 ◽

Cited By ~ 2

Author(s):

Raj Kamal Srivastava ◽

Annalena Moliner ◽

Ee-Soo Lee ◽

Emily Nickles ◽

Eunice Sim ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Cold Exposure ◽

Uncoupling Protein ◽

Surface Protein ◽

Negative Regulator ◽

Subcutaneous White Adipose Tissue ◽

Brown Adipose ◽

Beige Adipocytes ◽

A Cell

Prolonged cold exposure stimulates the formation of brownlike adipocytes expressing UCP1 (uncoupling-protein-1) in subcutaneous white adipose tissue which, together with classical brown adipose tissue, contributes to maintaining body temperature in mammals through nonshivering thermogenesis. The mechanisms that regulate the formation of these cells, alternatively called beige or brite adipocytes, are incompletely understood. Here we report that mice lacking CD137, a cell surface protein used in several studies as a marker for beige adipocytes, showed elevated levels of thermogenic markers, including UCP1, increased numbers of beige adipocyte precursors, and expanded UCP1-expressing cell clusters in inguinal white adipose tissue after chronic cold exposure. CD137 knockout mice also showed enhanced cold resistance. These results indicate that CD137 functions as a negative regulator of “browning” in white adipose tissue and call into question the use of this protein as a functional marker for beige adipocytes.

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Cold-induced lipid dynamics and transcriptional programs in white adipose tissue

BMC Biology ◽

10.1186/s12915-019-0693-x ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 9

Author(s):

Ziye Xu ◽

Wenjing You ◽

Yanbing Zhou ◽

Wentao Chen ◽

Yizhen Wang ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Fatty Acid ◽

White Adipose Tissue ◽

Cold Exposure ◽

Fatty Acid Elongation ◽

Rna Seq ◽

Short Term ◽

Lipid Dynamics ◽

Expression Of Genes

Abstract Background In mammals, cold exposure induces browning of white adipose tissue (WAT) and alters WAT gene expression and lipid metabolism to boost adaptive thermogenesis and maintain body temperature. Understanding the lipidomic and transcriptomic profiles of WAT upon cold exposure provides insights into the adaptive changes associated with this process. Results Here, we applied mass spectrometry and RNA sequencing (RNA-seq) to provide a comprehensive resource for describing the lipidomic or transcriptome profiles in cold-induced inguinal WAT (iWAT). We showed that short-term (3-day) cold exposure induces browning of iWAT, increases energy expenditure, and results in loss of body weight and fat mass. Lipidomic analysis shows that short-term cold exposure leads to dramatic changes of the overall composition of lipid classes WAT. Notably, cold exposure induces significant changes in the acyl-chain composition of triacylglycerols (TAGs), as well as the levels of glycerophospholipids and sphingolipids in iWAT. RNA-seq and qPCR analysis suggests that short-term cold exposure alters the expression of genes and pathways involved in fatty acid elongation, and the synthesis of TAGs, sphingolipids, and glycerophospholipids. Furthermore, the cold-induced lipid dynamics and gene expression pathways in iWAT are contrary to those previously observed in metabolic syndrome, neurodegenerative disorders, and aging, suggesting beneficial effects of cold-induced WAT browning on health and lifespan. Conclusion We described the significant alterations in the composition of glyphospholipids, glycerolipids, and sphingolipids and expression of genes involved in thermogenesis, fatty acid elongation, and fatty acid metabolism during the response of iWAT to short-term cold exposure. We also found that some changes in the levels of specific lipid species happening after cold treatment of iWAT are negatively correlated to metabolic diseases, including obesity and T2D.

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The involvement of neuroimmune cells in adipose innervation

10.21203/rs.3.rs-66882/v2 ◽

2020 ◽

Author(s):

Magdalena Blaszkiewicz ◽

Elizabeth Wood ◽

Sigi Koizar ◽

Jake Willows ◽

Ryan Anderson ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Cold Exposure ◽

Immune Cells ◽

Neurotrophic Factors ◽

Neurotrophic Factor ◽

Stromal Vascular Fraction ◽

Proper Function ◽

Cold Stimulation ◽

Myeloid Lineage

Abstract Background: Innervation of adipose tissue is essential for the proper function of this critical metabolic organ. Numerous surgical and chemical denervation studies have demonstrated how maintenance of brain-adipose communication through both sympathetic efferent and sensory afferent nerves help regulate adipocyte size, cell number, lipolysis, and ‘browning’ of white adipose tissue. Neurotrophic factors are growth factors that promote neuron survival, regeneration, and plasticity, including neurite outgrowth and synapse formation. Peripheral immune cells have been shown to be a source of neurotrophic factors in humans and mice. Although a number of immune cells reside in the adipose stromal vascular fraction (SVF), it has remained unclear what roles they play in adipose innervation. We previously demonstrated that adipose SVF secretes brain derived neurotrophic factor (BDNF). Methods: We now show that deletion of this neurotrophic factor from the myeloid lineage of immune cells led to a ‘genetic denervation’ of inguinal subcutaneous white adipose tissue (scWAT), thereby causing decreased energy expenditure, increased adipose mass, and a blunted UCP1 response to cold stimulation. Results: We and others have previously shown that noradrenergic stimulation via cold exposure increases adipose innervation in the inguinal depot. Here we have identified a subset of myeloid cells that home to scWAT upon cold exposure and are Ly6C+ CCR2+ Cx3CR1+ monocytes/macrophages that express noradrenergic receptors and BDNF. This subset of myeloid lineage cells also clearly interacted with peripheral nerves in the scWAT and were therefore considered neuroimmune cells. Conclusions: We propose that these myeloid lineage, cold induced neuroimmune cells (CINCs) are key players in maintaining adipose innervation as well as promoting adipose nerve remodeling under noradrenergic stimulation, such as cold exposure.

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Spexin Friend or Foe? Novel Role of Spexin During Thermogenesis of White Adipose Tissue

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.117 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A58-A58

Author(s):

Sabrina E Gambaro ◽

Guillermina Maria Zubiria ◽

Alejandra P Giordano ◽

Ezequiel A Harnichar ◽

Andrea E Portales ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Cold Exposure ◽

Interaction Effect ◽

Caloric Intake ◽

Relative Mass ◽

Diabetic Patients ◽

Cold Stimulation

Abstract Spexin (SPX) is a novel adipokine playing an emerging role in metabolic diseases due to its involvement in carbohydrate homeostasis, weight loss, appetite control, gastrointestinal movement, among others. Moreover, plasma levels are reduced in obese and type II diabetic patients. In vitro, SPX favors lipolysis in adipocytes and hepatocytes and inhibits white adipogenesis. Therefore, the aim of this study was to evaluate the role of SPX in white adipose tissue (AT) thermogenesis. C57BL/6J male mice were treated or not with SPX for ten days (ip. 29 µg/kg/day; CTR and SPX). At day 3 mice were randomly divided: a group was kept at room temperature (RT) and the other at 4°C to stimulate thermogenesis (CTR-C and SPX-C). Caloric intake and body weight was daily recorded. At the end of the protocol plasma, Brown AT (BAT), abdominal AT (Epidydimal, EAT) and subcutaneous AT (Inguinal, IAT) depots were collected for several measurements. We found that caloric intake was increased when animals were exposed to cold (P<0.001). Body weight change revealed a differential effect of SPX depending on temperature (interaction SPX x Cold, P<0.05): SPX animals weighted less than CTR at RT, but upon cold stimulation there was no difference. No changes were observed for plasma glucose levels, however plasma triglycerides (Tg) levels decreased after cold exposure regardless SPX treatment (Cold P<0.01). Liver Tg content showed a SPX x Cold interaction effect (P<0.0001), where, upon cold stimulation, CTR-C animals increased their levels, but on the contrary SPX-C mice decreased it. EAT, IAT and BAT relative mass showed an interaction effect of variables (SPX x Cold P<0.05). When compared upon cold, SPX-C mice had less AT mass compared to CTR-C mice. IAT and EAT mRNA expression of UCP1 and Cox8b showed SPX x Cold interaction (P<0.05), with a tendency of reduction or no difference in SPX at RT, but with a significant decrease in SPX-C compared to CTR-C mice upon cold exposure. PGC1a expression was increased in EAT from cold exposed-mice and in IAT only in CTR-C mice. UCP1 protein levels showed different results depending on the AT depot. For IAT SPX x Cold interaction (P<0.05) was observed, where SPX inhibited UCP1 stimulation only upon cold exposure. On the contrary, for EAT UCP1 levels decreased in SPX-treated mice, regardless cold exposure (SPX P<0.05). In conclusion, SPX treatment in vivo reduced the thermogenic process in subcutaneous and abdominal AT, being more evident upon cold stimulation. PICT2017-2038, PICT2017-2314.

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Increased expression level of ANGPTL8 in white adipose tissue under acute and chronic cold treatment

Lipids in Health and Disease ◽

10.1186/s12944-021-01547-0 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Hossein Arefanian ◽

Irina Al-Khairi ◽

Nermeen Abu Khalaf ◽

Preethi Cherian ◽

Sina Kavalakatt ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Cold Exposure ◽

Uncoupling Protein ◽

Cold Treatment ◽

Control Group ◽

Initial Increase ◽

Mrna Levels ◽

Brown Adipose

Abstract Background Angiopoietin-like proteins (ANGPTL), primarily 3, 4, and 8, play a major role in maintaining energy homeostasis by regulating triglyceride metabolism. This study evaluated the level of ANGPTL3, 4, and 8 in the liver, brown adipose tissue (BAT), and subcutaneous white adipose tissue (SAT) of mice maintained under acute and chronic cold conditions. Methods C57BL/6J mice were exposed to cold temperature (4 °C) for 10 days with food provided ad libitum. Animal tissues were harvested at Day 0 (Control group, n = 5) and Days 1, 3, 5, and 10 (cold treatment groups, n = 10 per group). The expression levels of various genes were measured in the liver, SAT, and BAT. ANGPTL3, 4, and 8 expressions were measured in the liver. ANGPTL4, 8, and genes involved in browning and lipid metabolism [uncoupling protein 1 (UCP1), lipoprotein lipase (LPL), and adipose triglyceride lipase (ATGL)] were measured in SAT and BAT. Western blotting (WB) analysis and immunohistochemistry (IHC) were performed to confirm ANGPTL8 expression in these tissues. Results The expressions of ANGPTL3 and 8 mRNA were significantly reduced in mouse liver tissues after cold treatment (P < 0.05); however, the expression of ANGPTL4 was not significantly altered. In BAT, ANGPTL8 expression was unchanged after cold treatment, whereas ANGPTL4 expression was significantly reduced (P < 0.05). ANGPTL4 levels were also significantly reduced in SAT, whereas ANGPTL8 gene expression exhibited over a 5-fold increase. Similarly, UCP1 gene expression was also significantly increased in SAT. The mRNA levels of LPL and ATGL showed an initial increase followed by a gradual decrease with an increase in the days of cold exposure. ANGPTL8 protein overexpression was further confirmed by WB and IHC. Conclusions This study shows that exposure to acute and chronic cold treatment results in the differential expression of ANGPTL proteins in the liver and adipose tissues (SAT and BAT). The results show a significant reduction in ANGPTL4 in BAT, which is linked to improved thermogenesis in response to acute cold exposure. ANGPTL8 was activated under acute and chronic cold conditions in SAT, suggesting that it is involved in regulating lipolysis and enhancing SAT browning.

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Transcriptional Response of Subcutaneous White Adipose Tissue to Acute Cold Exposure in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms20163968 ◽

2019 ◽

Vol 20 (16) ◽

pp. 3968 ◽

Cited By ~ 4

Author(s):

Xiaojuan Liang ◽

Jianfei Pan ◽

Chunwei Cao ◽

Lilan Zhang ◽

Ying Zhao ◽

...

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

White Adipose Tissue ◽

Cold Exposure ◽

Transcriptional Response ◽

Metabolic Process ◽

Transcriptional Analysis ◽

Subcutaneous White Adipose Tissue ◽

Acute Cold Exposure ◽

Go Terms

Beige adipose tissue has been considered to have potential applications in combating obesity and its related metabolic diseases. However, the mechanisms of acute cold-stimulated beige formation still remain largely unknown. Here, transcriptional analysis of acute cold-stimulated (4 °C for 4 h) subcutaneous white adipose tissue (sWAT) was conducted to determine the molecular signatures that might be involved in beige formation. Histological analysis confirmed the appearance of beige adipocytes in acute cold-treated sWAT. The RNA-sequencing data revealed that 714 genes were differentially expressed (p-value < 0.05 and fold change > 2), in which 221 genes were upregulated and 493 genes were downregulated. Gene Ontology (GO) analyses showed that the upregulated genes were enriched in the GO terms related to lipid metabolic process, fatty acid metabolic process, lipid oxidation, fatty acid oxidation, etc. In contrast, downregulated genes were assigned the GO terms of regulation of immune response, regulation of response to stimulus, defense response, etc. The expressions of some browning candidate genes were validated in cold-treated sWAT and 3T3-L1 cell browning differentiation. In summary, our results illustrated the transcriptional response of sWAT to acute cold exposure and identified the genes, including Acad11, Cyp2e1, Plin5, and Pdk2, involved in beige adipocyte formation in mice.

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