bims-mimbat 2022-05-22 papers

bims-mimbat

Biomed News

on Mitochondrial metabolism in brown adipose tissue

Issue of 2022–05–22
twelve papers selected by
José Carlos de Lima-Júnior, University of California San Francisco

Comparative multi-tissue profiling reveals extensive tissue-specificity in transcriptome reprogramming during thermal adaptation.
Cold exposure and the metabolism of mice, men, and other wonderful creatures.
Pantothenate protects against obesity via brown adipose tissue activation.
Deletion of GPR30 Drives the Activation of Mitochondrial Uncoupling Respiration to Induce Adipose Thermogenesis in Female Mice.
Can we target obesity using a single-cell atlas of adipose tissue?
Spexin modulates molecular thermogenic profile of adipose tissue and thermoregulatory behaviors in female C57BL/6 mice.
Mitochondrial TrxR2 regulates metabolism and protects from metabolic disease through enhanced TCA and ETC function.
TRPC5 deletion in the central amygdala antagonizes high-fat diet-induced obesity by increasing sympathetic innervation.
Notch ankyrin domain: evolutionary rise of a thermodynamic sensor.
Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment.
Calorie restriction and calorie dilution have different impacts on body fat, metabolism, behavior, and hypothalamic gene expression.
Differential effects of acute versus chronic dietary fructose consumption on metabolic responses in FVB/N mice.

Elife. 2022 May 17. pii: e78556. [Epub ahead of print]11

Comparative multi-tissue profiling reveals extensive tissue-specificity in transcriptome reprogramming during thermal adaptation.

Noushin Hadadi, Martina Spiljar, Karin Steinbach, Melis Çolakoğlu, Claire Chevalier, Gabriela Salinas, Doron Merkler, Mirko Trajkovski.

  Thermal adaptation is an extensively used intervention for enhancing or suppressing thermogenic and mitochondrial activity in adipose tissues. As such, it has been suggested as a potential lifestyle intervention for body weight maintenance. While the metabolic consequences of thermal acclimation are not limited to the adipose tissues, the impact on the rest of the tissues in context of their gene expression profile remains unclear. Here, we provide a systematic characterization of the effects in a comparative multi-tissue RNA sequencing approach following exposure of mice to 10 °C, 22 °C, or 34 °C in a panel of organs consisting of spleen, bone marrow, spinal cord, brain, hypothalamus, ileum, liver, quadriceps, subcutaneous-, visceral- and brown adipose tissues. We highlight that transcriptional responses to temperature alterations exhibit a high degree of tissue-specificity both at the gene level and at GO enrichment gene sets, and show that the tissue-specificity is not directed by the distinct basic gene expression pattern exhibited by the various organs. Our study places the adaptation of individual tissues to different temperatures in a whole-organism framework and provides integrative transcriptional analysis necessary for understanding the temperature-mediated biological programming.

Keywords:  adipose tissue; cold; computational biology; genetics; genomics; metabolism; mouse; multi-tissue transcriptomics; systems biology; temperature; warm

DOI:  https://doi.org/10.7554/eLife.78556
Physiology (Bethesda). 2022 May 16.

Cold exposure and the metabolism of mice, men, and other wonderful creatures.

Alicia J Kowaltowski.

  Laboratory rodents and cold-adapted animals in the wild use a significant amount of the energy derived from food intake for heat generation. Thermogenesis involving mitochondrial uncoupling in the brown adipose tissue differs quantitatively in mice, men, and cold-adapted animals, and could be an important ally to combat obesity, if humans were prepared to deviate slightly from thermoneutral living conditions to activate this pathway.

Keywords:  Metabolism; cold exposure; mitochondrial uncoupling

DOI:  https://doi.org/10.1152/physiol.00002.2022
Am J Physiol Endocrinol Metab. 2022 May 16.

Pantothenate protects against obesity via brown adipose tissue activation.

Huiqiao Zhou, Hanlin Zhang, Rongcai Ye, Chunlong Yan, Jun Lin, Yuanyuan Huang, Xiaoxiao Jiang, Shouli Yuan, Li Chen, Rui Jiang, Kexin Zheng, Ziyu Cheng, Zhi Zhang, Meng Dong, Wanzhu Jin.

  Brown adipose tissue (BAT) is the primary site of adaptive thermogenesis, which is involved in energy expenditure and has received much attention in the field of obesity treatment. By screening a small-molecular library of Food and Drug Administration approved drugs, pantothenic acid was identified as being able to significantly upregulate the expression of uncoupling protein 1 (UCP1), a key thermogenic protein found in BAT. Pantothenate (PA) treatment decreased adiposity, reversed fatty liver and improved glucose homeostasis via increased energy expenditure in C57BL/6J mice fed a high-fat diet. PA could also increase BAT activity and induce beige formation. Mechanistically, the beneficial effects were evidently mediated by UCP1, because PA treatment was unable to ameliorate the obesity in UCP1 knockout mice. In conclusion, we identified PA as a safe and effective BAT activator that can reduce obesity and may represent a promising strategy for the clinical treatment of obesity and related metabolic diseases.

Keywords:  Brown Adipose Tissue; Obesity; Pantothenate; Pantothenic Acid; Uncoupling Protein 1

DOI:  https://doi.org/10.1152/ajpendo.00293.2021
Front Endocrinol (Lausanne). 2022 ;13 877152

Deletion of GPR30 Drives the Activation of Mitochondrial Uncoupling Respiration to Induce Adipose Thermogenesis in Female Mice.

Jing Luo, Yao Wang, Elizabeth Gilbert, Dongmin Liu.

  Thermogenic adipocytes possess a promising approach to combat obesity with its capability promoting energy metabolism. We previously discovered that deletion of GPR30 (GPRKO), a presumably membrane-associated estrogen receptor, protected female mice from developing obesity, glucose intolerance, and insulin resistance when challenged with a high-fat diet (HFD). In vivo, the metabolic phenotype of wild type (WT) and GPRKO female mice were measured weekly. Acute cold tolerance test was performed. Ex vivo, mitochondrial respiration of brown adipose tissue (BAT) was analyzed from diet-induced obese female mice of both genotypes. In vitro, stromal vascular fractions (SVF) were isolated for beige adipocyte differentiation to investigate the role of GPR30 in thermogenic adipocyte. Deletion of GPR30 protects female mice from hypothermia and the mitochondria in BAT are highly energetic in GPRKO animals while the WT mitochondria remain in a relatively quiescent stage. Consistently, GPR30 deficiency enhances beige adipocyte differentiation in white adipose tissue (WAT) and activates the thermogenic browning of subcutaneous WAT due to up-regulation of UCP-1, which thereby protects female mice from HFD-induced obesity. GPR30 is a negative regulator of thermogenesis, which at least partially contributes to the reduced adiposity in the GPRKO female mice. Our findings provide insight into the mechanism by which GPR30 regulates fat metabolism and adiposity in female mice exposed to excess calories, which may be instrumental in the development of new therapeutic strategies for obesity.

Keywords:  GPR30; fatty acid oxidation; female mice; mitochondrial respiration; thermogenesis

DOI:  https://doi.org/10.3389/fendo.2022.877152
Med (N Y). 2022 May 13. pii: S2666-6340(22)00172-6. [Epub ahead of print]3(5): 276-278

Can we target obesity using a single-cell atlas of adipose tissue?

Camilla Scheele, Søren Nielsen.

Adipose tissue is a multicellular tissue with depot-dependent functions including safe energy storage and release, immune defense, thermogenesis, and organ padding. Emont et al. zoom in on white adipose tissue at a single-cell resolution and provide an extensive resource for future insights in how to target obesity.1.

DOI: https://doi.org/10.1016/j.medj.2022.04.006
Horm Behav. 2022 May 14. pii: S0018-506X(22)00089-7. [Epub ahead of print]143 105195

Spexin modulates molecular thermogenic profile of adipose tissue and thermoregulatory behaviors in female C57BL/6 mice.

Shermel B Sherman, Mitchell Harberson, Rebecca Rashleigh, Niraj Gupta, Riley Powers, Ramya Talla, Ashima Thusu, Jennifer W Hill.

  Thermoregulation is the physiological process by which an animal regulates body temperature in response to its environment. It is known that galanin, a neuropeptide widely distributed throughout the central nervous system and secreted by the gut, plays a role in thermoregulatory behaviors and metabolism. We tested the ability of the novel neuropeptide spexin, which shares sequence homology to galanin, to regulate these functions in female mice. Supraphysiological levels of spexin in C57BL/6 mice did not lead to weight loss after 50 days of treatment. Behavioral analysis of long-term spexin treatment showed it decreased anxiety and increased thermoregulatory nest building, which was not observed when mice were housed at thermoneutral temperatures. Treatment also disrupted the thermogenic profile of brown and white adipose tissue, decreasing mRNA expression of Ucp1 in BAT and immunodetection of β3-adrenergic receptors in gWAT. Our results reveal novel functions for spexin as a modulator of thermoregulatory behaviors and adipose tissue metabolism.

Keywords:  Brown adipose tissue; Nest building; Neuropeptide; Spexin; Thermogenesis

DOI:  https://doi.org/10.1016/j.yhbeh.2022.105195
Commun Biol. 2022 May 16. 5(1): 467

Mitochondrial TrxR2 regulates metabolism and protects from metabolic disease through enhanced TCA and ETC function.

E Sandra Chocron, Kennedy Mdaki, Nisi Jiang, Jodie Cropper, Andrew M Pickering.

Mitochondrial dysfunction is a key driver of diabetes and other metabolic diseases. Mitochondrial redox state is highly impactful to metabolic function but the mechanism driving this is unclear. We generated a transgenic mouse which overexpressed the redox enzyme Thioredoxin Reductase 2 (TrxR2), the rate limiting enzyme in the mitochondrial thioredoxin system. We found augmentation of TrxR2 to enhance metabolism in mice under a normal diet and to increase resistance to high-fat diet induced metabolic dysfunction by both increasing glucose tolerance and decreasing fat deposition. We show this to be caused by increased mitochondrial function which is driven at least in part by enhancements to the tricarboxylic acid cycle and electron transport chain function. Our findings demonstrate a role for TrxR2 and mitochondrial thioredoxin as metabolic regulators and show a critical role for redox enzymes in controlling functionality of key mitochondrial metabolic systems.

DOI: https://doi.org/10.1038/s42003-022-03405-w
Int J Obes (Lond). 2022 May 20.

TRPC5 deletion in the central amygdala antagonizes high-fat diet-induced obesity by increasing sympathetic innervation.

Huan Ma, Chengkang He, Li Li, Peng Gao, Zongshi Lu, Yingru Hu, Lijuan Wang, Yu Zhao, Tingbing Cao, Yuanting Cui, Hongting Zheng, Gangyi Yang, Zhencheng Yan, Daoyan Liu, Zhiming Zhu.

Transient receptor potential channel 5 (TRPC5) is predominantly distributed in the brain, especially in the central amygdala (CeA), which is closely associated with pain and addiction. Although mounting evidence indicates that the CeA is related to energy homeostasis, the possible regulatory effect of TRPC5 in the CeA on metabolism remains unclear. Here, we reported that the expression of TRPC5 in the CeA of mice was increased under a high-fat diet (HFD). Specifically, the deleted TRPC5 protein in the CeA of mice using adeno-associated virus resisted HFD-induced weight gain, accompanied by increased food intake. Furthermore, the energy expenditure of CeA-specific TRPC5 deletion mice (TRPC5 KO) was elevated due to augmented white adipose tissue (WAT) browning and brown adipose tissue (BAT) activity. Mechanistically, deficiency of TRPC5 in the CeA boosted nonshivering thermogenesis under cold stimulation by stimulating sympathetic nerves, as the β3-adrenoceptor (Adrb3) antagonist SR59230A blocked the effect of TRPC5 KO on this process. In summary, TRPC5 deletion in the CeA alleviated the metabolic deterioration of mice fed a HFD, and these phenotypic improvements were correlated with the increased sympathetic distribution and activity of adipose tissue.

DOI: https://doi.org/10.1038/s41366-022-01151-x
Cell Commun Signal. 2022 May 18. 20(1): 66

Notch ankyrin domain: evolutionary rise of a thermodynamic sensor.

Filip Vujovic, Neil Hunter, Ramin M Farahani.

  Notch signalling pathway plays a key role in metazoan biology by contributing to resolution of binary decisions in the life cycle of cells during development. Outcomes such as proliferation/differentiation dichotomy are resolved by transcriptional remodelling that follows a switch from Notchon to Notchoff state, characterised by dissociation of Notch intracellular domain (NICD) from DNA-bound RBPJ. Here we provide evidence that transitioning to the Notchoff state is regulated by heat flux, a phenomenon that aligns resolution of fate dichotomies to mitochondrial activity. A combination of phylogenetic analysis and computational biochemistry was utilised to disclose structural adaptations of Notch1 ankyrin domain that enabled function as a sensor of heat flux. We then employed DNA-based micro-thermography to measure heat flux during brain development, followed by analysis in vitro of the temperature-dependent behaviour of Notch1 in mouse neural progenitor cells. The structural capacity of NICD to operate as a thermodynamic sensor in metazoans stems from characteristic enrichment of charged acidic amino acids in β-hairpins of the ankyrin domain that amplify destabilising inter-residue electrostatic interactions and render the domain thermolabile. The instability emerges upon mitochondrial activity which raises the perinuclear and nuclear temperatures to 50 °C and 39 °C, respectively, leading to destabilization of Notch1 transcriptional complex and transitioning to the Notchoff state. Notch1 functions a metazoan thermodynamic sensor that is switched on by intercellular contacts, inputs heat flux as a proxy for mitochondrial activity in the Notchon state via the ankyrin domain and is eventually switched off in a temperature-dependent manner. Video abstract.

Keywords:  Ankyrin; Heat flux; Mitochondria; Notch1

DOI:  https://doi.org/10.1186/s12964-022-00886-4
Nat Commun. 2022 May 19. 13(1): 2769

Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment.

Enrique Balderas, David R Eberhardt, Sandra Lee, John M Pleinis, Salah Sommakia, Anthony M Balynas, Xue Yin, Mitchell C Parker, Colin T Maguire, Scott Cho, Marta W Szulik, Anna Bakhtina, Ryan D Bia, Marisa W Friederich, Timothy M Locke, Johan L K Van Hove, Stavros G Drakos, Yasemin Sancak, Martin Tristani-Firouzi, Sarah Franklin, Aylin R Rodan, Dipayan Chaudhuri.

Calcium entering mitochondria potently stimulates ATP synthesis. Increases in calcium preserve energy synthesis in cardiomyopathies caused by mitochondrial dysfunction, and occur due to enhanced activity of the mitochondrial calcium uniporter channel. The signaling mechanism that mediates this compensatory increase remains unknown. Here, we find that increases in the uniporter are due to impairment in Complex I of the electron transport chain. In normal physiology, Complex I promotes uniporter degradation via an interaction with the uniporter pore-forming subunit, a process we term Complex I-induced protein turnover. When Complex I dysfunction ensues, contact with the uniporter is inhibited, preventing degradation, and leading to a build-up in functional channels. Preventing uniporter activity leads to early demise in Complex I-deficient animals. Conversely, enhancing uniporter stability rescues survival and function in Complex I deficiency. Taken together, our data identify a fundamental pathway producing compensatory increases in calcium influx during Complex I impairment.

DOI: https://doi.org/10.1038/s41467-022-30236-4
Cell Rep. 2022 May 17. pii: S2211-1247(22)00608-8. [Epub ahead of print]39(7): 110835

Calorie restriction and calorie dilution have different impacts on body fat, metabolism, behavior, and hypothalamic gene expression.

Xue Liu, Zengguang Jin, Stephanie Summers, Davina Derous, Min Li, Baoguo Li, Li Li, John R Speakman.

  Caloric restriction is a robust intervention to increase lifespan. Giving less food (calorie restriction [CR]) or allowing free access to a diluted diet with indigestible components (calorie dilution [CD]) are two methods to impose restriction. CD does not generate the same lifespan effect as CR. We compare responses of C57BL/6 mice with equivalent levels of CR and CD. The two groups have different responses in fat loss, circulating hormones, and metabolic rate. CR mice are hungrier, as assessed by behavioral assays. Although gene expression of Npy, Agrp, and Pomc do not differ between CR and CD groups, CR mice had a distinctive hypothalamic gene-expression profile with many genes related to starvation upregulated relative to CD. While both result in lower calorie intake, CR and CD are not equivalent procedures. Increased hunger under CR supports the hypothesis that hunger signaling is a key process mediating the benefits of CR.

Keywords:  CP: Metabolism; behavior; body fat; caloric restriction; diluted diet; energy expenditure; hunger; hypothalamus; lifespan; metabolic effects; physical activity

DOI:  https://doi.org/10.1016/j.celrep.2022.110835
Am J Physiol Regul Integr Comp Physiol. 2022 May 17.

Differential effects of acute versus chronic dietary fructose consumption on metabolic responses in FVB/N mice.

Jordan W Strober, Sully Fernandez, Honggang Ye, Matthew J Brady.

  Increased human consumption of hgh fructose corn syrup has been linked to the marked increase in obesity and metabolic syndrome. Previous studies on the rapid effects of a high fructose diet in mice have largely been confined to the C57Bl6 strains. In the current studied, the FVB/N strain of mice that are resistant to diet induced weight gain were utilized and fed a control or high fructose diet for 48 hours or 12 weeks. Many of the previously reported changes that occurred upon high fructose feeding for 48 hours in C57Bl6 mice were recapitulated in the FVB/N mice. However, the acute increases in fructolytic and lipogenic gene expression were completely lost during the 12 week dietary intervention protocol. Furthermore, there was no significant weight gain in FVB/N mice fed a high fructose diet for 12 weeks, despite an overall increase in caloric consumption and an increase in average epididymal adipocyte cell size. These findings may be in part explained by a commensurate increase in energy expenditure and in carbohydrate utilization in high fructose fed animals. Overall, these findings demonstrate that FVB/N mice are a suitable model for the study of the effects of dietary intervention on metabolic and molecular parameters. Furthermore, the rapid changes in hepatic gene expression that have been widely reported were not sustained over a longer time course. Compensatory changes in energy expenditure and utilization may be in part responsible for the differences obtained between acute and chronic high fructose feeding protocols.

Keywords:  Adipose Tissue Secretome; Energy Expenditure; Hepatic Gene Expression; High Fructose Corn Syrup

DOI:  https://doi.org/10.1152/ajpregu.00174.2021