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| Open AccessLipopolysaccharide binding protein resists hepatic oxidative stress by regulating lipid droplet homeostasis
Oxidative stress triggers lipid accumulation in cells by sequestering triglycerides in lipid droplets. Here, the authors show that lipopolysaccharide-binding protein interacts with redox sensor PRDX4 to control lipid-redox balance and promotes triglyceride accumulation in droplets by capturing unsaturated lipids.
- Qilun Zhang
- , Xuting Shen
- & Haoshu Fang
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Article
| Open AccessPaternal dietary macronutrient balance and energy intake drive metabolic and behavioral differences among offspring
The dietary factors causing varying intergenerational responses are not fully identified. Here, the authors show that the relative proportion of protein, fats, and carbohydrates in paternal diets before conception differentially influences the phenotype of the next-generation offspring on energy metabolism and behaviour.
- Angela Jane Crean
- , Alistair McNair Senior
- & Stephen James Simpson
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Article
| Open AccessCold-induced FOXO1 nuclear transport aids cold survival and tissue storage
How tissues adapt to extreme cold is not well understood. Here, the authors discover a mechanism that promotes FOXO1-mediated cold survival gene transcription at low temperatures, with potential implications for long-term tissue storage for transplantation.
- Xiaomei Zhang
- , Lihao Ge
- & Jingxing Ou
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Article
| Open AccessObesity-related T cell dysfunction impairs immunosurveillance and increases cancer risk
Obesity represents a risk factor for cancer and compromises immune function, however the mechanisms linking the two together are not fully known. Here authors show in a mouse sarcoma model that obesity increases tumour incidence, impairs intra-tumoral T cell immunity but paradoxically increases sensitivity to immune therapy via impairing immunoediting.
- Alexander Piening
- , Emily Ebert
- & Ryan M. Teague
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Article
| Open AccessInvolution of brown adipose tissue through a Syntaxin 4 dependent pyroptosis pathway
Aging, chronic high-fat diet feeding, or housing at thermoneutrality induces brown adipose tissue (BAT) involution. Here, the authors demonstrate that physiologic aging induced involution and thermogenic dysfunction result from pyroptotic signalling activation.
- Xiaofan Yu
- , Gabrielle Benitez
- & Daorong Feng
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Article
| Open AccessTM4SF19-mediated control of lysosomal activity in macrophages contributes to obesity-induced inflammation and metabolic dysfunction
Adipose tissue adapts to overnutrition in a complex process, wherein specialized immune cells remove and replace dysfunctional and stressed adipocytes with new fat cells. Here, the authors show that the deletion of TM4SF19 expressed in lipid-associated macrophages, enhances the clearance of dying adipocytes, thereby improving local and systemic insulin sensitivity as well as energy expenditure.
- Cheoljun Choi
- , Yujin L. Jeong
- & Yun-Hee Lee
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Article
| Open AccessNaked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles
The naked mole-rat exhibits extreme longevity, resistance to hypoxia and absence of cardiovascular disease. Here, Faulkes et al. identify mechanisms behind these traits by comparing cardiac metabolomes and transcriptomes of naked more-rats to other African mole-rat genera and evolutionary divergent mammals.
- Chris G. Faulkes
- , Thomas R. Eykyn
- & Dunja Aksentijevic
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Article
| Open AccessActivation of the insulin receptor by insulin-like growth factor 2
IGF2 has a distinct binding affinity for two insulin receptor (IR) isoforms and mimics insulin’s function. Here, the authors present the activation mechanism of IR by IGF2 and reveal the molecular basis for IGF2’s different affinity for two IR isoforms.
- Weidong An
- , Catherine Hall
- & Eunhee Choi
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Article
| Open AccessSNX8 enables lysosome reformation and reverses lysosomal storage disorder
Lysosomal storage disorders (LSDs) are severe genetic diseases currently without routine therapies. Here, the authors identified that SNX8 participates in lysosome reformation and serves as a potential drug target for new therapies to treat LSDs.
- Xinran Li
- , Cong Xiang
- & Xin-Hua Feng
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Article
| Open AccessTrimethylamine N-oxide impairs β-cell function and glucose tolerance
β-Cell dysfunction is a hallmark of type 2 diabetes. Here, the authors show that trimethylamine N-oxide (TMAO (a microbiota metabolite)) induces β-cell dysfunction and type 2 diabetes in mice through NLRP3 inflammasome activation and calcium transients.
- Lijuan Kong
- , Qijin Zhao
- & Pingping Li
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Article
| Open AccessHepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver
The liver is segregated into spatially organized areas that serve distinct functions, though how these zones are patterned remains unclear. Here they show that mTORC1 controls spatial segregation of liver metabolic functions via modulation of Wnt signaling, and find that impaired zonation is also observed in pigs given total parenteral nutrition.
- Ana Belén Plata-Gómez
- , Lucía de Prado-Rivas
- & Alejo Efeyan
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Article
| Open AccessmicroRNA-33 controls hunger signaling in hypothalamic AgRP neurons
AgRP neurons regulate feeding behavior by promoting signals of hunger. Here, the authors show that miR-33, represses the activity of AgRP neurons, and selective loss of miR-33 in AgRP neurons promotes obesity and metabolic dysfunction in mice.
- Nathan L. Price
- , Pablo Fernández-Tussy
- & Carlos Fernández-Hernando
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Article
| Open AccessNDUFS4 regulates cristae remodeling in diabetic kidney disease
Mitochondrial Ndufs4, a subunit of complex I, is a regulator of the electron transport chain. Here, the authors show that forced expression of Ndufs4 in podocytes improves the assembly of respiratory supercomplexes, maintains cristae integrity, and mitigates the progression of diabetic kidney disease
- Koki Mise
- , Jianyin Long
- & Farhad R. Danesh
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Article
| Open AccessA spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling
Kang et al. reveal structural and functional differences in mitochondria across the hepatic lobule. Mitochondrial distinct phosphoproteome influences their functions highlighting how nutrient availability helps to shape mitochondria zonation.
- Sun Woo Sophie Kang
- , Rory P. Cunningham
- & Natalie Porat-Shliom
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Article
| Open AccessAdipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape
Adipose tissue (AT) inflammation is strongly associated with obesity and constitutes an obesogenic memory upon weight loss. Here, the authors show that intermittent fasting leads to an adipocyte p53-signaling dependent emergence of lipid-associated macrophages in visceral AT of obese mice which limits the systemic fasting response.
- Isabel Reinisch
- , Helene Michenthaler
- & Andreas Prokesch
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Article
| Open AccessPolar bear energetic and behavioral strategies on land with implications for surviving the ice-free period
Declining Arctic sea ice is increasing polar bear land use. Here, the authors follow 20 different polar bears on land over 3 years and measure daily energy expenditure finding that despite behavioural and diet plasticity the bears are at risk of starvation.
- Anthony M. Pagano
- , Karyn D. Rode
- & Charles T. Robbins
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Article
| Open AccessProtection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R
Overfeeding triggers a mechanistically ill-defined compensatory response that counteracts weight gain. Here, the authors show that the defence against overfeeding is preserved in obesity, and that it is independent from FGF21 and MC4R.
- Camilla Lund
- , Pablo Ranea-Robles
- & Christoffer Clemmensen
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Article
| Open AccessThe impact of reproductive factors on the metabolic profile of females from menarche to menopause
Here, the authors explore the relation between age at menarche, parity and age at natural menopause with 249 metabolic traits in over 65,000 UK Biobank to explore whether reproductive factors are likely to impact females’ metabolic profile later in life.
- Gemma L. Clayton
- , Maria Carolina Borges
- & Deborah A. Lawlor
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Article
| Open AccessRelaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status
Restoring mitochondrial function has emerged as a promising therapeutic strategy for diabetic retinopathy. Here, the authors show that mitochondrial hyperfusion blunts mitophagy during the disease process, and that rescuing this process pharmacologically confers retinal neuroprotection independent of an improved glycaemic status in type-1 diabetic mice.
- Aidan Anderson
- , Nada Alfahad
- & Jose R. Hombrebueno
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Article
| Open AccessArtesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signalling axis
Obesity is a global health challenge with an ongoing need for new medical treatments. Here, the authors show that artesunate, an FDA-approved treatment for severe malaria, can be repurposed for the treatment of obesity via GDF15/GFRAL signaling axis without overt side effects in mice and non-human primates.
- Xuanming Guo
- , Pallavi Asthana
- & Hoi Leong Xavier Wong
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Article
| Open AccessSecretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone homeostasis in mice
The mechanism by which central secretin regulates metabolism is unclear. Here, the authors show that ventromedial hypothalamus-derived secretin maintains energy and bone homeostasis by controlling food intake and sympathetic nerve activity.
- Fengwei Zhang
- , Wei Qiao
- & Billy Kwok Chong Chow
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Article
| Open AccessUbiquitin 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 AccessUpregulated hepatic lipogenesis from dietary sugars in response to low palmitate feeding supplies brain palmitate
The origin of brain palmitic acid (PAM) has been debated. Here, by using natural abundance carbon isotope ratios and RNA sequencing the authors show that the majority of brain PAM is maintained by hepatic PAM synthesis from dietary sugars during development and is upregulated in mice fed low PAM.
- Mackenzie E. Smith
- , Chuck T. Chen
- & Richard P. Bazinet
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Article
| Open AccessAmyloid beta 42 alters cardiac metabolism and impairs cardiac function in male mice with obesity
Epidemiological evidence has identified associations among obesity, Alzheimer’s disease, and cardiovascular disease. Here, the authors report that adipose tissue releases amyloid beta 42 (Aβ42) and that antagonizing Aβ42 protects cardiac function in obesity murine models.
- Liam G. Hall
- , Juliane K. Czeczor
- & Sean L. McGee
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Article
| Open AccessDiabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila
The mechanisms underlying diabetic neuropathy remain elusive. Here, the authors identify that UCHL1 deubiquitinase positively regulates insulin signaling and its loss leads to axonal degeneration of sensory neurons.
- Daewon Lee
- , Eunju Yoon
- & Jongkyeong Chung
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Article
| Open AccessMuscle abnormalities worsen after post-exertional malaise in long COVID
In this longitudinal, case-controlled, cohort design study, authors show that post-exertional malaise is associated with severe exercise-induced myopathy, local and systemic metabolic disturbances and infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID.
- Brent Appelman
- , Braeden T. Charlton
- & Rob C. I. Wüst
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Article
| Open AccessSurplus 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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Article
| Open AccessApoL6 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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Article
| Open AccessMtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis
Excessive lipid accumulation in hepatocytes causes fatty liver disease and liver failure. Here the authors show that ablation of Mitochondrial Fission Process 1 in hepatocytes in mice protects fatty liver disease and dysfunction caused by high fat diet.
- Cecilia Patitucci
- , Juan Diego Hernández-Camacho
- & Timothy Wai
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Article
| Open AccessFunctional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing
Spatially resolved metabolism in complex tissues is vital but poorly understood. Here, the authors establish the Drosophila renal system as a paradigm for linking mechanistic analysis of metabolism at single-cell resolution to organ-wide physiology.
- Jack Holcombe
- & Helen Weavers
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Article
| Open AccessFunctional and analytical recapitulation of osteoclast biology on demineralized bone paper
Here, authors report demineralized bone paper-based in vitro osteogenic culture and assay platforms that replicate essential bone tissue complexity, osteoclast processes, and drug responses with high fidelity and predictive power.
- Yongkuk Park
- , Tadatoshi Sato
- & Jungwoo Lee
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Article
| Open AccessEarly-adult methionine restriction reduces methionine sulfoxide and extends lifespan in Drosophila
Dietary methionine restriction extends lifespans in many organisms. Here, the authors show in Drosophila that methionine restriction in early adulthood can increase lifespan and that the beneficial effect of the dietary manipulation declines with age.
- Hina Kosakamoto
- , Fumiaki Obata
- & Masayuki Miura
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Article
| Open AccessSkeletal muscle-secreted DLPC orchestrates systemic energy homeostasis by enhancing adipose browning
MyoD is a transcription factor expressed in skeletal muscle that plays a critical role in determining myogenic cell fate. Here, Hu et al. reveal a metabolic role of MyoD in orchestrating systemic energy homeostasis by mediating muscle-fat crosstalk through the muscle-secreted lipokine DLPC.
- Xiaodi Hu
- , Mingwei Sun
- & Dahai Zhu
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Article
| Open AccessModulation of insulin secretion by RBFOX2-mediated alternative splicing
Insulin secretion from the pancreatic beta cell is a tightly regulated process that is vital for maintaining blood glucose homeostasis. Here, the authors show that the RNA binding protein RBFOX2 is a regulator of insulin secretion through the alternative splicing of genes required for insulin granule docking and exocytosis.
- Nicole D. Moss
- , Kristen L. Wells
- & Lori Sussel
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Article
| Open AccessA distinct Acyl-CoA binding protein (ACBP6) shapes tissue plasticity during nutrient adaptation in Drosophila
Plasticity in tissue function and morphology is shaped by adaptive responses to nutrient changes. Here, the authors found that a putative calibration of acyl-CoA and acetyl-CoA metabolism through ACBP6 is crucial for Drosophila intestine’s proliferative homeostasis in response to nutrient changes.
- Xiaotong Li
- & Jason Karpac
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Article
| Open AccessFNIP1 abrogation promotes functional revascularization of ischemic skeletal muscle by driving macrophage recruitment
Functional revascularization is vital to the recovery of blood flow. Here, Sun et al. show that myofiber FNIP1 is a negative regulator of muscle functional angiogenesis and revascularization after ischemia by controlling macrophage recruitment.
- Zongchao Sun
- , Likun Yang
- & Zhenji Gan
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Article
| Open AccessTranscriptional repression of beige fat innervation via a YAP/TAZ-S100B axis
Sympathetic innervation is essential for the development of functional beige fat that maintains metabolic homeostasis. Qiu and colleagues discover that YAP/TAZ can act as a brake on the beige fat innervation by blocking PRDM16-C/EBPβ-mediated S100b expression.
- Xun Huang
- , Xinmeng Li
- & Yifu Qiu
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Article
| Open AccessSpliceosome component Usp39 contributes to hepatic lipid homeostasis through the regulation of autophagy
Non-alcoholic fatty liver disease affects 25% of people worldwide. Here the authors report that spliceosome component Usp39 deletion in mice leads to spontaneous steatosis and impaired autophagy through the regulation of alternative splicing.
- Donghai Cui
- , Zixiang Wang
- & Zhaojian Liu
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Article
| Open AccessHepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression in male mice
NASH, nonalcoholic steatohepatitis, a severe fatty liver disease with no cure, can manifest through loss-of-function of the E3 ligase FBXW7. Here, the authors show an underpinning of dysregulated ERRα and PPARα nuclear receptor activity, thus highlighting potential new avenues for antiNASH therapy.
- Hui Xia
- , Catherine R. Dufour
- & Vincent Giguère
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Article
| Open AccessGenome-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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Article
| Open AccessMaternal 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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Article
| Open AccessLipocalin 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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Article
| Open AccessEndogenous renal adiponectin drives gluconeogenesis through enhancing pyruvate and fatty acid utilization
Adiponectin is a widely studied secretory protein produced by adipocytes. Here, the authors show that adiponectin is also expressed in the kidney where it is a major driver of fatty acid oxidation, from which the kidney derives energy for gluconeogenesis.
- Toshiharu Onodera
- , May-Yun Wang
- & Philipp E. Scherer
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Article
| Open AccessPPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy
The mitochondrial phosphatase PPTC7 has previously been linked to the maintenance of mitochondrial content, but the mechanisms underlying this phenotype remain unclear. Here, the authors demonstrate that loss of Pptc7 results in metabolic defects and further suggest that PPTC7 is a regulator of receptor-mediated mitophagy.
- Natalie M. Niemi
- , Lia R. Serrano
- & David J. Pagliarini
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Article
| Open AccessPalmitoylation-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 AccessFAM210A 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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Article
| Open AccessComprehensive assessment of physiological responses in women during the ESA dry immersion VIVALDI microgravity simulation
To consider the impact of sex on adaptation to space, the European Space Agency initiated VIVALDI dry immersion microgravity simulation in female subjects. Here, the authors show marked deconditioning with 5-day exposure, and propose comprehensive multi-system physiological assessment in 18 healthy women.
- Adrien Robin
- , Angelique Van Ombergen
- & Nastassia Navasiolava
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Article
| Open AccessMulti-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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Article
| Open AccessTMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis
Mitochondrial dynamics affect the thermogenic capacity of brown adipose tissue. Here, the authors show that TMEM135 regulates thermogenesis and energy homeostasis by mediating mitochondrial fission in brown adipocytes.
- Donghua Hu
- , Min Tan
- & Irfan J. Lodhi