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Rab30 facilitates lipid homeostasis during fasting
Despite the importance of Rab GTPases in maintaining the integrity of vesicle trafficking, their physiological roles are not well understood. Here, the authors define a role for Rab30 in supporting lipid homeostasis during fasting in the mouse.
- Danielle M. Smith
- , Brian Y. Liu
- & Michael J. Wolfgang
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| Open Access
A nutrient responsive lipase mediates gut-brain communication to regulate insulin secretion in Drosophila
Amplification of glucose stimulated insulin secretion by lipids is not fully understood due to complex inter organ communication in glycemic regulation. Here the authors show Vaha, a Drosophila lipase synthesized in the gut, concentrates in insulin producing cells in the brain to regulate insulin like peptide release.
- Alka Singh
- , Kandahalli Venkataranganayaka Abhilasha
- & Usha R. Acharya
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Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling
The peroxisomal β-oxidation enzyme ACOX1 increases in liver with obesity, but the physiological significance is unclear. Here, the authors show that liver-specific knockout of Acox1 leads to accumulation of omega-3 VLCFAs that promote metabolic health through activation of GPR120 in adipose tissue.
- Dongliang Lu
- , Anyuan He
- & Irfan J. Lodhi
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Comparison of intramyocellular lipid metabolism in patients with diabetes and male athletes
Endurance athletes and sedentary type 2 diabetes patients swapped their lifestyle for 8 weeks. Athletes store and utilise saturated fat intensely for performant physical activity, and type 2 diabetes patients reversed their dysmetabolic lipid state after endurance training.
- Alice M. Mezincescu
- , Amelia Rudd
- & Dana Dawson
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Ubiquitin ligase RNF20 coordinates sequential adipose thermogenesis with brown and beige fat-specific substrates
Upon cold exposure, two types of thermogenic fat cells, brown and beige adipocytes, are sequentially activated. Here, the authors show that E3 ubiquitin ligase RNF20 coordinates the sequential thermogenic activation through fat depot specific substrates.
- Yong Geun Jeon
- , Hahn Nahmgoong
- & Jae Bum Kim
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Article
| Open Access
Surplus fatty acid synthesis increases oxidative stress in adipocytes and induces lipodystrophy
The physiological significance of low fatty acid synthesis in adipocytes remains unclear. Here, the authors show a protective role of this phenomenon by demonstrating that overproduction of fatty acids increases ROS production and results in adipocyte necroptosis and lipodystrophy.
- Li Weng
- , Wen-Shuai Tang
- & Tong-Jin Zhao
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ApoL6 associates with lipid droplets and disrupts Perilipin1-HSL interaction to inhibit lipolysis
Lipolysis in adipose tissue releases fatty acids during fasting. Here, authors show that ApoL6, a lipid droplet-associated protein, is specifically expressed in adipocytes upon feeding to inhibit lipolysis by directly interacting with Perilipin 1 to competitively inhibit Perilipin 1-HSL interaction.
- Yuhui Wang
- , Hai P. Nguyen
- & Hei S. Sul
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Genome-wide association analysis of plasma lipidome identifies 495 genetic associations
The human plasma lipidome captures risk for cardiometabolic diseases. Here, the authors perform univariate and multivariate genome-wide analyses of 179 lipid species in 7174 Finnish individuals, revealing genetic links between diseases and lipid species beyond the standard lipids HDL-Cholesterol, LDL-Cholesterol, Triglycerides, and total Cholesterol.
- Linda Ottensmann
- , Rubina Tabassum
- & Matti Pirinen
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| Open Access
Maternal thyroid hormone receptor β activation in mice sparks brown fat thermogenesis in the offspring
Maternal thyroid hormone is important for fetal development. Here, the authors show that hyperthyroidism during pregnancy can program the offsprings’ glucose sensitivity and response to cold via activation of maternal thyroid hormone receptor β in a sex dependent manner
- Rebecca Oelkrug
- , Lisbeth Harder
- & Jens Mittag
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| Open Access
Lipocalin 2 regulates mitochondrial phospholipidome remodeling, dynamics, and function in brown adipose tissue in male mice
Mitochondrial function is essential for energy metabolism in brown adipocytes. Here, the authors show that LCN2 plays a critical role as a phosphatidic acid binding protein in phospholipid acyl chain remodeling and mitochondrial bioenergetics, influencing signaling pathway activation.
- Hongming Su
- , Hong Guo
- & Xiaoli Chen
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| Open Access
Palmitoylation-driven PHF2 ubiquitination remodels lipid metabolism through the SREBP1c axis in hepatocellular carcinoma
Palmitoylation of proteins can have pathophysiological implications. Here, the authors show that palmitoylation enhances the proteasomal degradation of the histone demethylase PHF2, leading to increased lipogenesis and cell proliferation in an SREBP1c dependent manner and further show that PHF2 acts as an E3 ligase of SREBP1c, suppressing the growth of liver cancer cells.
- Do-Won Jeong
- , Jong-Wan Park
- & Yang-Sook Chun
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Article
| Open Access
FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes
Mammalians rely on brown adipocytes to generate heat under cold exposure, this thermogenic function requires dynamic remodeling of the mitochondria. Here the authors identify a protein called FAM210A as a key regulator of cold-induced mitochondrial remodeling in brown adipocytes.
- Jiamin Qiu
- , Feng Yue
- & Shihuan Kuang
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| Open Access
Multi-omics profiling reveals rhythmic liver function shaped by meal timing
Post-translational modifications (PTMs) couple feed-fast cycles to circadian clocks. Here, the authors systematically profile daily rhythms of the proteome, 4 PTMs and lipidome in mouse livers under TRF, providing a comprehensive resource detailing rhythmic liver functions shaped by meal timing.
- Rongfeng Huang
- , Jianghui Chen
- & Min-Dian Li
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Cold-activated brown fat-derived extracellular vesicle-miR-378a-3p stimulates hepatic gluconeogenesis in male mice
During cold exposure, activated brown adipose tissue takes up a large amount of circulating glucose to fuel thermogenesis. Here, the authors show that cold stress enhances the packaging of miR-378a-3p into BAT-derived EVs, which are delivered to the liver and consequently stimulates gluconeogenesis.
- Jinhong Xu
- , Le Cui
- & Xiaohong Jiang
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| Open Access
Bone marrow adiposity modulation after long duration spaceflight in astronauts
Bone marrow adiposity is linked to disease, and it is unknown how it is modulated during space travel. Here, the authors show that astronauts returning from ISS missions had decreased marrow fat and increased hematopoiesis and bone formation, suggesting that adipose reserves in the bone marrow might be used as an energy source to counteract anemia and bone loss associated with space flight.
- Tammy Liu
- , Gerd Melkus
- & Guy Trudel
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Determining the metabolic effects of dietary fat, sugars and fat-sugar interaction using nutritional geometry in a dietary challenge study with male mice
The role of dietary fat vs sugar in the global obesity epidemic remains controversial. Using Nutritional Geometry methodology, the authors show that, in mice, both fats and sugars could lead to adverse metabolic outcomes, depending on the dietary context.
- Jibran A. Wali
- , Duan Ni
- & Stephen J. Simpson
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| Open Access
Linker histone variant H1.2 is a brake on white adipose tissue browning
Thermogenic adipocytes are ideal targets to counteract obesity and associated metabolic disorders. Here, the authors show a regulatory role of linker histone variant H1.2 on iWAT browning and thermogenesis through an H1.2-IL10rα axis.
- Yangmian Yuan
- , Yu Fan
- & Ling Zheng
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| Open Access
Gut microbiota Turicibacter strains differentially modify bile acids and host lipids
Mechanisms by which the gut microbiota affects its host are a main research focus. Here, Lynch et al. characterize bile acid modifications performed by a prevalent bacterial taxon from the gut, the genus Turicibacter, and found they broadly altered host lipids, connecting Turicibacter functions and host physiology.
- Jonathan B. Lynch
- , Erika L. Gonzalez
- & Elaine Y. Hsiao
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| Open Access
Endothelial cell-derived stem cell factor promotes lipid accumulation through c-Kit-mediated increase of lipogenic enzymes in brown adipocytes
Although it is known that cellular crosstalk between endothelial cells and brown adipocytes is essential, it remains poorly understood. Here the authors show that SCF derived from the surrounding endothelial cells promotes lipid accumulation in BAT by enhancing lipogenic enzymes in through c-Kit activation.
- Hyuek Jong Lee
- , Jueun Lee
- & Gou Young Koh
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Male reproductive traits are differentially affected by dietary macronutrient balance but unrelated to adiposity
We know that nutrition and obesity can impact male fertility, but specific dietary guidelines for men trying to conceive don’t exist. Here the authors show that diet composition is likely more important than body fat in influencing reproductive traits and each macronutrient has different impacts.
- A. J. Crean
- , S. Afrin
- & T. Pini
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The rhythmic coupling of Egr-1 and Cidea regulates age-related metabolic dysfunction in the liver of male mice
Many transcriptomic pathways in the liver show circadian rhythms, which have been reported to be disrupted in aged mice. Here the authors report that the expression of transcription factor Egr-1 decreases and its rhythm is shifted with age in the liver of male mice, and that deletion of Egr-1 results in increased liver fat accumulation.
- Jing Wu
- , Dandan Bu
- & Chao-Jun Li
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| Open Access
Adipocyte YTH N(6)-methyladenosine RNA-binding protein 1 protects against obesity by promoting white adipose tissue beiging in male mice
Activation of white adipose tissue (WAT) thermogenesis alleviates obesity-associated metabolic disorders in rodents. Here the authors report that the m6 A RNA modification reader YTHDF1 promotes WAT thermogenesis in a study with male mice, and may be a potential target for the treatment of obesity.
- Sujun Yan
- , Xiaoling Zhou
- & Xiangwei Gao
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| Open Access
De novo lipogenesis fuels adipocyte autophagosome and lysosome membrane dynamics
The function of de novo lipogenesis (DNL) in adipocytes has been a mystery as it contributes little to fat storage in these cells. Here, the authors show that DNL is a critical source of fatty acids for membrane-expanding processes like autophagy.
- Leslie A. Rowland
- , Adilson Guilherme
- & Michael P. Czech
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| Open Access
Increased adipose catecholamine levels and protection from obesity with loss of Allograft Inflammatory Factor-1
Macrophages have been reported to regulate thermogenic, sympathetic neuron-mediated norepinephrine signaling in adipose tissues. Here the authors report that male mice lacking the allograft inflammatory factor-1 protein are resistant to diet-induced obesity, in association with higher adipose norepinephrine levels and lower expression of the norepinephrine catabolic enzyme monoamine oxidase A.
- Prameladevi Chinnasamy
- , Isabel Casimiro
- & Nicholas E. S. Sibinga
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| Open Access
A brown fat-enriched adipokine Adissp controls adipose thermogenesis and glucose homeostasis
The signaling mechanisms regulating adipose thermogenesis have not been fully elucidated. Here, the authors show that a brown fat-enriched adipokine ADISSP promotes adipose thermogenesis and improves metabolic health independently of b-adrenergic receptor.
- Qingbo Chen
- , Lei Huang
- & Yong-Xu Wang
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| Open Access
Osteoblast/osteocyte-derived interleukin-11 regulates osteogenesis and systemic adipogenesis
Here, the authors identify interleukin-11 as a mediator of bone-adipose crosstalk during mechanical loading of the bone. Interleukin-11 secreted by the bone acts as a hormone to regulate fat metabolism, in addition to having an autocrine-paracrine effect on bone itself.
- Bingzi Dong
- , Masahiro Hiasa
- & Toshio Matsumoto
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Sphingosine 1-phosphate mediates adiponectin receptor signaling essential for lipid homeostasis and embryogenesis
Cells and organisms requires proper membrane composition, which the cell must modulate as membrane lipids are primary acquired from the diet. Here, Ruiz et al. identify a conserved pathway connecting the fluidity regulators AdipoR1/2 with fatty acid desaturase SCD to mediate membrane homeostasis.
- Mario Ruiz
- , Ranjan Devkota
- & Marc Pilon
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Phosphorylation of 17β-hydroxysteroid dehydrogenase 13 at serine 33 attenuates nonalcoholic fatty liver disease in mice
A truncating variant of 17β-hydroxysteroid dehydrogenase-13 (17β-HSD13), a lipid droplet -associated protein, associates with lower risk of chronic liver disease. Here the authors identify a phosphorylation site in 17β-HSD13 which promotes lipolysis, and report that a knock-in mouse with a 17β-HSD13 mutant defective for phosphorylation is more susceptible to nonalcoholic steatohepatitis.
- Wen Su
- , Sijin Wu
- & Youfei Guan
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| Open Access
TLCD1 and TLCD2 regulate cellular phosphatidylethanolamine composition and promote the progression of non-alcoholic steatohepatitis
The regulation of cellular phosphatidylethanolamine (PE) acyl chain composition is poorly understood. Here, the authors show that TLCD1 and TLCD2 proteins mediate the formation of monounsaturated fatty acid-containing PE species and promote the progression of non-alcoholic steatohepatitis.
- Kasparas Petkevicius
- , Henrik Palmgren
- & Xiao-Rong Peng
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| Open Access
Chronic intake of high dietary sucrose induces sexually dimorphic metabolic adaptations in mouse liver and adipose tissue
Dietary sugar intake may contribute to the development non-alcoholic fatty liver disease. Here the authors investigated the effects of chronic dietary sucrose on the liver-adipose-microbiome axis in mice, and report that sex is a moderating factor that influences sucrose-driven lipid storage in the liver and adipose tissue lipolysis.
- Erin J. Stephenson
- , Amanda S. Stayton
- & Joan C. Han
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Article
| Open Access
SARS-CoV-2 infects adipose tissue in a fat depot- and viral lineage-dependent manner
Visceral adiposity is a risk factor for severe COVID-19, and infection of adipose tissue by SARS-CoV-2 has been reported. Here the authors confirm that human adipose tissue is a possible site for SARS-CoV-2 infection, but the degree of adipose tissue infection and the way adipocytes respond to the virus depend on the adipose tissue depot and the viral strain.
- Tatiana Dandolini Saccon
- , Felippe Mousovich-Neto
- & Marcelo A. Mori
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TFEB regulates sulfur amino acid and coenzyme A metabolism to support hepatic metabolic adaptation and redox homeostasis
Matye el al. show that coenzyme-A and glutathione deficiency in NAFLD limits fatty acid oxidation and antioxidant defence capacity. The nutrient sensing transcription factor EB induces autophagy–lysosome proteolysis and methionine cycle-transsulfuration to maintain hepatic cysteine, coenzyme-A and glutathione availability.
- David Matye
- , Sumedha Gunewardena
- & Tiangang Li
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| Open Access
Fatty acids homeostasis during fasting predicts protection from chemotherapy toxicity
Fasting has been reported to protect from chemotherapy-associated toxicity. Here, the authors show that fatty acid profiles in erythrocyte membranes and gene expression from peripheral blood mononuclear cells are associated to the fasting-mediated benefits during cancer treatment in mice and patients.
- Marta Barradas
- , Adrián Plaza
- & Pablo J. Fernandez-Marcos
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| Open Access
No evidence of brown adipose tissue activation after 24 weeks of supervised exercise training in young sedentary adults in the ACTIBATE randomized controlled trial
Exercise modulates brown adipose tissue (BAT) metabolism in murine models. Here the authors report that there is no evidence that 24 weeks of supervised exercise training modulates BAT volume or function in young sedentary adults in the ACTIBATE randomized controlled trial.
- Borja Martinez-Tellez
- , Guillermo Sanchez-Delgado
- & Jonatan R. Ruiz
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| Open Access
Loss of immunity-related GTPase GM4951 leads to nonalcoholic fatty liver disease without obesity
Obesity is a major risk factor for fatty liver disease. Here, using a forward genetic screen, the authors identify the gene GM4951 as a GTPase involved in lipid oxidation and development of NAFLD in mice.
- Zhao Zhang
- , Yu Xun
- & Bruce Beutler
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| Open Access
Adipocyte lysoplasmalogenase TMEM86A regulates plasmalogen homeostasis and protein kinase A-dependent energy metabolism
Dysregulation of plasmalogen metabolism in adipose tissue is associated with metabolic diseases. Here the authors characterize the role of adipocyte TMEM86A as a lysoplasmalogenase and show its deletion is protective against high fat diet induced metabolic disease, an effect that can be recapitulated by plasmenyl lysophosphatidylethanolamine 18:0 supplementation.
- Yoon Keun Cho
- , Young Cheol Yoon
- & Yun-Hee Lee
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Article
| Open Access
TRIM24 is an insulin-responsive regulator of P-bodies
Insulin promotes hepatic lipogenesis, though underlying regulation remains unclear. Here the authors show that insulin translocates TRIM24 from the nucleus into cytosolic P-bodies to stabilise hepatic Pparγ mRNA, and that inactivation of TRIM24 promotes Pparγ degradation and alleviates hepatosteatosis.
- Wen Wei
- , Qiaoli Chen
- & Shuai Chen
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Article
| Open Access
Adipocyte-derived kynurenine promotes obesity and insulin resistance by activating the AhR/STAT3/IL-6 signaling
Kynurenine, a tryptophan metabolite, is increased in the circulating plasma of obese individuals, but the source has been unclear. Here, the authors show in mice that mature adipocytes produce kynurenine, with vitamin B6 administration preventing accumulation and protecting against high-fat diet.
- Teng Huang
- , Jia Song
- & Cong-Yi Wang
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Article
| Open Access
Adipocyte HIF2α functions as a thermostat via PKA Cα regulation in beige adipocytes
Thermogenic adipocytes maintain body temperature in response to cold, but how this is tuned during cold and re-warming is unclear. Here, the authors show HIF2α inhibits beige adipocyte retention, regulating PKA catalysis to control dynamic adipocyte remodelling.
- Ji Seul Han
- , Yong Geun Jeon
- & Jae Bum Kim
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Article
| Open Access
The long noncoding RNA ADIPINT regulates human adipocyte metabolism via pyruvate carboxylase
Adipocyte-expressed long non-coding RNAs (lncRNAs) have been shown to regulate the transcription of genes involved in lipid metabolism. Here the authors describe a human adipocyte-specific lncRNA, ADIPINT, which regulates lipid metabolism in white adipocytes in part through its interaction with the metabolic enzyme pyruvate carboxylase.
- Alastair G. Kerr
- , Zuoneng Wang
- & Hui Gao
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Article
| Open Access
Statin therapy inhibits fatty acid synthase via dynamic protein modifications
Statin therapy is associated with numerous cellular effects. Here, the authors show that statin treatment increases post-translational modifications on fatty acid synthase in the active site, revealing communication between the cholesterol and lipid biosynthetic pathways.
- Alec G. Trub
- , Gregory R. Wagner
- & Matthew D. Hirschey
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| Open Access
Mitochondrially targeted tamoxifen alleviates markers of obesity and type 2 diabetes mellitus in mice
Senescent cells play a role in pathogenesis of diabetes, and senolytic agents can improve obesity- and diabetes-related pathologies. Here the authors report that mitochondrially targeted tamoxifen, a potential anti-cancer agent with senolytic activity, alleviates symptoms of obesity and prediabetes in mice, potentially via reduction of food intake and elimination of senescent cells.
- Eliska Vacurova
- , Jaroslava Trnovska
- & Jiri Neuzil
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Article
| Open Access
Deep proteomic profiling unveils arylsulfatase A as a non-alcoholic steatohepatitis inducible hepatokine and regulator of glycemic control
Non-alcoholic steatohepatitis (NASH) and type 2 diabetes are closely linked, but the connecting pathophysiological mechanisms are incompletely understood. Here the authors identify arylsulfatase A as a NASH-induced hepatokine that inhibits hepatic lysophosphatidylcholine and lysophosphatidic acid secretion, and improves muscle insulin action and systemic glucose homeostasis.
- Magdalene K. Montgomery
- , Jacqueline Bayliss
- & Matthew J. Watt
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Article
| Open Access
Caffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance
Caffeine may reduce cardiovascular disease risk, but the underlying mechanisms for these effects are incompletely understood. Here the authors report that caffeine inhibits the activation of the transcription factor SREBP2 to promote LDLc clearance through the PCSK9-LDLR axis.
- Paul F. Lebeau
- , Jae Hyun Byun
- & Richard C. Austin
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Article
| Open Access
The transcription factor hepatocyte nuclear factor 4A acts in the intestine to promote white adipose tissue energy storage
HNF4A is a nuclear receptor that regulates liver lipid homeostasis. Here the authors show that HNF4A is not required for intestinal lipid metabolism but controls energy expenditure under diet induced obesity through the fat-induced release of glucose-dependent insulinotropic polypeptide.
- Romain Girard
- , Sarah Tremblay
- & François Boudreau
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Article
| Open Access
Lipid droplet availability affects neural stem/progenitor cell metabolism and proliferation
Lipid droplets (LDs) are central to lipid metabolism, which is known to regulate neural stem cell behavior. Here, the authors show that LDs influence neural stem cell proliferation and metabolic activity and change upon differentiation or quiescence.
- Mergim Ramosaj
- , Sofia Madsen
- & Marlen Knobloch
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Article
| Open Access
Free fatty-acid transport via CD36 drives β-oxidation-mediated hematopoietic stem cell response to infection
Hematopoietic stem cells (HSCs) rapidly expand upon infection, switching their metabolic profile to increase OXPHOS. Here, the authors show in mouse models that infection promotes uptake of long-chain free fatty acids via CD36, which is required for a protective response.
- Jayna J. Mistry
- , Charlotte Hellmich
- & Stuart A. Rushworth
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Article
| Open Access
GPR180 is a component of TGFβ signalling that promotes thermogenic adipocyte function and mediates the metabolic effects of the adipocyte-secreted factor CTHRC1
Activation of thermogenic adipocytes is a strategy to combat metabolic diseases. Here the authors report that GPR180 is a component of TGFβ signalling that promotes thermogenic adipocyte function and mediates the metabolic effects of the adipocyte-secreted factor CTHRC1, and contributes to the regulation of glucose and energy metabolism.
- Lucia Balazova
- , Miroslav Balaz
- & Christian Wolfrum
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Article
| Open Access
High-intensity training induces non-stoichiometric changes in the mitochondrial proteome of human skeletal muscle without reorganisation of respiratory chain content
Exercise training can be therapeutic but how mitochondria respond remains unclear. Here, the authors use multiple omics techniques to reveal a complex network of non-stoichiometric mitochondrial adaptations that are prioritized or deprioritised during different phases of exercise training.
- Cesare Granata
- , Nikeisha J. Caruana
- & David J. Bishop
Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels