bims-mimbat 2022-03-20 papers

Cell Rep. 2022 Mar 15. pii: S2211-1247(22)00220-0. [Epub ahead of print]38(11): 110487

Cell-autonomous control of intracellular temperature by unsaturation of phospholipid acyl chains.

Akira Murakami, Kohjiro Nagao, Reiko Sakaguchi, Keisuke Kida, Yuji Hara, Yasuo Mori, Kohki Okabe, Yoshie Harada, Masato Umeda.

Intracellular temperature affects a wide range of cellular functions in living organisms. However, it remains unclear whether temperature in individual animal cells is controlled autonomously as a response to fluctuations in environmental temperature. Using two distinct intracellular thermometers, we find that the intracellular temperature of steady-state Drosophila S2 cells is maintained in a manner dependent on Δ9-fatty acid desaturase DESAT1, which introduces a double bond at the Δ9 position of the acyl moiety of acyl-CoA. The DESAT1-mediated increase of intracellular temperature is caused by the enhancement of F1Fo-ATPase-dependent mitochondrial respiration, which is coupled with thermogenesis. We also reveal that F1Fo-ATPase-dependent mitochondrial respiration is potentiated by cold exposure through the remodeling of mitochondrial cristae structures via DESAT1-dependent unsaturation of mitochondrial phospholipid acyl chains. Based on these findings, we propose a cell-autonomous mechanism for intracellular temperature control during environmental temperature changes.

Keywords: F(1)F(o)-ATPase; intracellular temperature; mitochondrial cristae; mitochondrial thermogenesis; phospholipid; Δ9-fatty acid desaturase

DOI: https://doi.org/10.1016/j.celrep.2022.110487

J Physiol. 2022 Mar 17.

AMP-activated protein kinase activation in skeletal muscle modulates exercise-induced uncoupled protein 1 expression in brown adipocyte in mouse model.

Hye Jin Kim, Youn Ju Kim, Je Kyung Seong.

KEY POINTS: Exercise promotes thermogenesis by activating uncoupling protein 1 (UCP1), which leads to a decrease in the body weight gain and body fat content. However, little is known about the role of exerkines in modulating UCP1 expression and subsequent brown adipose tissue (BAT) activation. Four weeks of voluntary wheel running exercise reduces body weight and fat content. Exercise induces the increase in AMP-activated protein kinase (AMPK) and slow-type muscle fibre marker genes in skeletal muscles and promotes UCP1 expression in white and brown adipose tissues. Incubation of brown adipocytes with serum isolated from exercise-trained mice significantly increased their UCP1 gene and protein levels; moreover, conditioned media of AMPK-activator-treated C2C12 myotubes induces increased UCP1 expression in brown adipocytes. These results highlight that aerobic exercise-induced skeletal muscle AMPK has a significant effect on UCP1 expression in BAT.
ABSTRACT: Aerobic exercise is an effective intervention in preventing obesity and is, also an important factor associated with thermogenesis. There is an increasing interest in factors and mechanisms induced by aerobic exercise that can influence the metabolism and thermogenic activity in an individual. Recent studies suggest that exercise-induced circulating factors, which are (known as "exerkines") able to modulate activation of brown adipose tissue (BAT) and browning of white adipose tissue. However, the underlying molecular mechanisms associated with the effect of exercise-induced peripheral factors on BAT activation remain poorly understood. Furthermore, the role of exercise training in BAT activation is still debatable. Hence, the purpose of our study is to assess whether exercise training affects the expression of uncoupled protein 1 (UCP1) in brown adipocytes via release of different blood factors. Four weeks of exercise training significantly decreased the body weight gain and fat mass gain. Furthermore, trained mice exhibit higher levels of energy expenditure and UCP1 expression compared with untrained mice. Surprisingly, treatment with serum from exercise-trained mice increased the expression of UCP1 in differentiated brown adipocytes. To gain a better understanding of these mechanisms, we analysed the conditioned media obtained after treating the C2C12 myotubes with an AMP-activated protein kinase (AMPK) activator (AICAR; 5-aminoimidazole-4-carboxamide ribonucleotide), which leads to an increased expression of UCP1 when added to brown adipocytes. Our observations suggest the possibility of aerobic exercise-induced BAT activation via activation of AMPK in skeletal muscles. Abstract figure legend Exercise induces the release of several factors called 'exerkines' that can help to modulate the metabolic as well as thermogenic activity of an individual. However, there is limited knowledge regarding the underlying molecular mechanisms that enable these factors to stimulate brown adipose tissue activity. Our study demonstrates that exercise-induces activation of AMP-activated protein kinase in skeletal muscles, which, in turn, presumably through the release of exerkines from muscles, can modulate the uncoupled protein 1 expression in brown adipocytes. We believe that this paper provides an understanding of the molecular basis of adipocyte browning during aerobic exercise, and this knowledge may be useful in developing novel strategies for preventing the onset of/overcoming obesity. This article is protected by copyright. All rights reserved.

Keywords: AMPK; BAT activation; UCP1; brown adipocyte; exercise; exerkine; myokine

DOI: https://doi.org/10.1113/JP282999

Endocrinology. 2022 Mar 16. pii: bqac032. [Epub ahead of print]

Too much too soon - Tissue-specific inactivation of deiodinase type 3 prematurely exposes brown fat to thyroid hormone.

Rebecca Oelkrug, Jens Mittag.

Keywords: brown adipose tissue; deiodinase; development; thermogenesis; thyroid hormone

DOI: https://doi.org/10.1210/endocr/bqac032

Science. 2022 Mar 18. 375(6586): 1229-1231

Fueling the fire of adipose thermogenesis.

Christian Wolfrum, Zachary Gerhart-Hines.

Specialized fat tissue generates heat and holds the potential to counter metabolic diseases.

DOI: https://doi.org/10.1126/science.abl7108

J Lipid Res. 2022 Mar 14. pii: S0022-2275(22)00030-X. [Epub ahead of print] 100197

Determination of tissue contributions to the circulating lipid pool in cold exposure via systematic assessment of lipid profiles.

Raghav Jain, Gina Wade, Irene Ong, Bhagirath Chaurasia, Judith Simcox.

Plasma lipid levels are altered in chronic conditions such as type 2 diabetes and cardiovascular disease, as well as during acute stresses such as fasting and cold exposure. Advances in mass spectrometry-based lipidomics have uncovered a complex plasma lipidome of more than 500 lipids that serve functional roles, including as energy substrates and signaling molecules. This plasma lipid pool is maintained through regulation of tissue production, secretion, and uptake. A major challenge in understanding the lipidome complexity is establishing the tissues of origin and uptake for various plasma lipids, which is valuable for determining lipid functions. Using cold exposure as an acute stress, we performed global lipidomics on plasma and in nine tissues that may contribute to the circulating lipid pool. We found that numerous species of plasma acylcarnitines (ACars) and ceramides were significantly altered upon cold exposure. Through computational assessment, we identified the liver and brown adipose tissue (BAT) as major contributors and consumers of circulating ACars, in agreement with our previous work. We further identified the kidney and intestine as novel contributors to the circulating ACar pool and validated these findings with gene expression analysis. Regression analysis also identified that the BAT and kidney are interactors with the plasma ceramide pool. Taken together, these studies provide an adaptable computational tool to assess tissue contribution to the plasma lipid pool. Our findings have further implications in understanding the function of plasma ACars and ceramides, which are elevated in metabolic diseases.

Keywords: acylcarnitines; brown adipose tissue; ceramides; cold exposure; computational tool; lipidomics; mass spectrometry; metabolism; regression analysis; thermogenesis

DOI: https://doi.org/10.1016/j.jlr.2022.100197

Development. 2022 Mar 17. pii: dev.200260. [Epub ahead of print]

FOXP4 differentially controls cold-induced beige adipocyte differentiation and thermogenesis.

Fuhua Wang, Shuqin Xu, Tienan Chen, Shifeng Ling, Wei Zhang, Shaojiao Wang, Rujiang Zhou, Xuechun Xia, Zhengju Yao, Pengxiao Li, Xiaodong Zhao, Jiqiu Wang, Xizhi Guo.

Beige adipocytes possess a discrete developmental origin and notable plasticity in thermogenic capacity in response to various environmental cues. But the transcriptional machinery controlling beige adipocyte development and thermogenesis remains largely unknown. By analyzing beige adipocyte-specific knockout mice, we identified a transcription factor, Forkhead Box P4 (FOXP4) that differentially governs beige adipocyte differentiation and activation. Depletion of Foxp4 in progenitor cells impaired beige cell early differentiation. However, we observed that ablation of Foxp4 in differentiated adipocytes profoundly potentiated their thermogenesis upon cold exposure. Of note, the outcome of Foxp4-deficiency on UCP1-mediated thermogenesis was confined to beige adipocytes, rather than to brown adipocytes. Taken together, we submit that FOXP4 primes beige adipocyte early differentiation, but attenuates their activation by potent transcriptional repression of the thermogenic program.

Keywords: Beige adipocyte; Cell differentiation; FOXP4; Thermogenesis; Transcription factor

DOI: https://doi.org/10.1242/dev.200260

Diabetes. 2022 Mar 16. pii: db210799. [Epub ahead of print]

Impaired Cold Stimulated Supraclavicular Brown Adipose Tissue Activity in Young Boys with Obesity.

Basma A Ahmed, Nina Varah, Frank J Ong, Denis P Blondin, Elizabeth Gunn, Norman B Konyer, Nina P Singh, Michael D Noseworthy, Francois Haman, Andre C Carpentier, Zubin Punthakee, Gregory R Steinberg, Katherine M Morrison.

Childhood obesity is a growing worldwide problem. In adults, lower cold-induced brown adipose tissue (BAT) activity is linked to obesity and metabolic dysfunction; this relationship remains uncertain in children. In this cross-sectional study, we compared cold-induced supraclavicular (SCV) BAT activity (percent change in proton density fat fraction (PDFF) within the SCV region after one hour of whole-body cold exposure (18°C), using magnetic resonance imaging (MRI)) in 26 boys aged 8-10 years; 13 with normal body mass index (BMI), and 13 with overweight/obesity. Anthropometry, body composition, hepatic, and visceral fat (VAT), and pre- and post-cold PDFF of the subcutaneous adipose tissue (SAT) in the posterior neck region and the abdomen were measured. Boys with overweight/obesity had lower cold-induced percent decline in SCV PDFF compared to those with normal BMI (1.6±0.8 vs 4.7±1.2 , p=0.044). SCV PDFF declined significantly in boys with normal BMI (2.7±0.7 %, p=0.003) but not in boys with overweight/obesity (1.1±0.5%, p=0.053). No cold-induced changes in the PDFF of either the neck SAT (-0.89± 0.7 %, p= 0.250 vs 0.37 ± 0.3, p= 0.230) or the abdominal SAT (-0.39±0.5, p=0.409 and 0.25±0.2, p= 0.139 for normal BMI and overweight/obesity groups respectively) were seen. The cold-induced percent decline in SCV PDFF was inversely related to BMI (r=-0.39, p= 0.047), waist circumference (r= -0.48, p= 0.014), and VAT (r= -0.47, p= 0.014). Thus, in young boys, as in adults, BAT activity is lower in those with overweight/obesity, suggesting that restoring activity may be important for improving metabolic health.

DOI: https://doi.org/10.2337/db21-0799

Cell. 2022 Mar 17. pii: S0092-8674(22)00204-5. [Epub ahead of print]185(6): 941-943

Igniting adipocyte thermogenesis.

Raghav Jain, Judith Simcox.

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.

DOI: https://doi.org/10.1016/j.cell.2022.02.024

Elife. 2022 Mar 15. pii: e74334. [Epub ahead of print]11

Octopamine drives honeybee thermogenesis.

Sinan Kaya-Zeeb, Lorenz Engelmayer, Mara Straßburger, Jasmin Bayer, Heike Bähre, Roland Seifert, Oliver Scherf-Clavel, Markus Thamm.

In times of environmental change species have two options to survive: they either relocate to a new habitat or they adapt to the altered environment. Adaptation requires physiological plasticity and provides a selection benefit. In this regard, the Western honeybee (Apis mellifera) protrudes with its thermoregulatory capabilities, which enables a nearly worldwide distribution. Especially in the cold, shivering thermogenesis enables foraging as well as proper brood development and thus survival. In this study, we present octopamine signaling as a neurochemical prerequisite for honeybee thermogenesis: we were able to induce hypothermia by depleting octopamine in the flight muscles. Additionally, we could restore the ability to increase body temperature by administering octopamine. Thus, we conclude that octopamine signaling in the flight muscles is necessary for thermogenesis. Moreover, we show that these effects are mediated by β octopamine receptors. The significance of our results is highlighted by the fact the respective receptor genes underlie enormous selective pressure due to adaptation to cold climates. Finally, octopamine signaling in the service of thermogenesis might be a key strategy to survive in a changing environment.

Keywords: Apis mellifera; GPCR; glycolysis; honeybee; neuroscience; octopamine; thermogenesis

DOI: https://doi.org/10.7554/eLife.74334

Nature. 2022 Mar 16.

A single-cell atlas of human and mouse white adipose tissue.

White adipose tissue, once regarded as morphologically and functionally bland, is now recognized to be dynamic, plastic and heterogenous, and is involved in a wide array of biological processes including energy homeostasis, glucose and lipid handling, blood pressure control and host defence1. High-fat feeding and other metabolic stressors cause marked changes in adipose morphology, physiology and cellular composition1, and alterations in adiposity are associated with insulin resistance, dyslipidemia and type 2 diabetes2. Here we provide detailed cellular atlases of human and mouse subcutaneous and visceral white fat at single-cell resolution across a range of body weight. We identify subpopulations of adipocytes, adipose stem and progenitor cells, vascular and immune cells and demonstrate commonalities and differences across species and dietary conditions. We link specific cell types to increased risk of metabolic disease and provide an initial blueprint for a comprehensive set of interactions between individual cell types in the adipose niche in leanness and obesity. These data comprise an extensive resource for the exploration of genes, traits and cell types in the function of white adipose tissue across species, depots and nutritional conditions.

DOI: https://doi.org/10.1038/s41586-022-04518-2

Trends Biochem Sci. 2022 Mar 15. pii: S0968-0004(22)00050-0. [Epub ahead of print]

Integrating adipocyte insulin signaling and metabolism in the multi-omics era.

C Martinez Calejman, W G Doxsey, D J Fazakerley, D A Guertin.

Insulin stimulates glucose uptake into adipocytes via mTORC2/AKT signaling and GLUT4 translocation and directs glucose carbons into glycolysis, glycerol for TAG synthesis, and de novo lipogenesis. Adipocyte insulin resistance is an early indicator of type 2 diabetes in obesity, a worldwide health crisis. Thus, understanding the interplay between insulin signaling and central carbon metabolism pathways that maintains adipocyte function, blood glucose levels, and metabolic homeostasis is critical. While classically viewed through the lens of individual enzyme-substrate interactions, advances in mass spectrometry are beginning to illuminate adipocyte signaling and metabolic networks on an unprecedented scale, yet this is just the tip of the iceberg. Here, we review how 'omics approaches help to elucidate adipocyte insulin action in cellular time and space.

Keywords: glucose; insulin; metabolism; metabolomics; phosphoproteomics; white and brown adipose tissue

DOI: https://doi.org/10.1016/j.tibs.2022.02.009