Nature metabolism最新文献

The immune system plays a major role in the regulation of adipose tissue homeostasis. Viral infection often drives fat loss, but how and why this happens is unclear. Here, we show that visceral adipose tissue transiently decreases adiposity following viral infection. Upon pathogen encounter, adipose tissue upregulates surface expression of ligands for activating receptors on natural killer cells, which drives IFNγ secretion. This cytokine directly stimulates adipocytes to shift their balance from lipogenesis to lipolysis, which leads to release of lipids in circulation, most notably of free fatty acids. The free fatty acid oleic acid stimulates early-activated B cells by promoting oxidative phosphorylation. Oleic acid promoted expression of co-stimulatory B7 molecules on B cells and promoted their ability to prime CD8⁺ T cells. Inhibiting lipid uptake by activated B cells impaired CD8⁺ T cell responses, causing an increase of viral replication in vivo. Our findings uncover a previously unappreciated mechanism of metabolic adaptation to infection and provide a better understanding of the interactions between immune cells and adipose tissue in response to inflammation.

17β-oestradiol (E2) inhibits overeating and promotes brown adipose tissue (BAT) thermogenesis, whereas prolactin (PRL) does the opposite. During lactation, the simultaneous decline in E2 and surge in PRL contribute to maternal metabolic adaptations, including hyperphagia and suppressed BAT thermogenesis. However, the underlying neuroendocrine mechanisms remain unclear. Here, we find that oestrogen receptor alpha (ERα)-expressing neurons in the medial basal hypothalamus (MBH), specifically the arcuate nucleus of the hypothalamus and the ventrolateral subdivision of the ventromedial hypothalamus (vlVMH), are suppressed during lactation. Deletion of ERα from MBH neurons in virgin female mice induces metabolic phenotypes characteristic of lactation, including hyperprolactinemia, hyperphagia and suppressed BAT thermogenesis. By contrast, activation of ERα^vlVMH neurons in lactating mice attenuates these phenotypes. Overall, our study reveals an inhibitory effect of E2–ERα^vlVMH signalling on PRL production, which is suppressed during lactation to sustain hyperprolactinemia and metabolic adaptations.

Neurodegenerative diseases (NDDs) represent a heterogeneous group of disorders characterized by progressive neuronal loss, which results in significant deficits in memory, cognition, motor skills, and sensory functions. As the prevalence of NDDs rises, there is an urgent unmet need for effective therapies. Current drug development approaches primarily target single pathological features of the disease, which could explain the limited efficacy observed in late-stage clinical trials. Originally developed for the treatment of obesity and diabetes, incretin-based therapies, particularly long-acting GLP-1 receptor (GLP-1R) agonists and GLP-1R–gastric inhibitory polypeptide receptor (GIPR) dual agonists, are emerging as promising treatments for NDDs. Despite limited conclusive preclinical evidence, their pleiotropic ability to reduce neuroinflammation, enhance neuronal energy metabolism and promote synaptic plasticity positions them as potential disease-modifying NDD interventions. In anticipation of results from larger clinical trials, continued advances in next-generation incretin mimetics offer the potential for improved brain access and enhanced neuroprotection, paving the way for incretin-based therapies as a future cornerstone in the management of NDDs.

The mitochondrial unfolded protein response (UPR^mt), a mitochondria-to-nucleus retrograde pathway that promotes the maintenance of mitochondrial function in response to stress, plays an important role in promoting lifespan extension in Caenorhabditis elegans^1,2. However, its role in mammals, including its contributions to development or cell fate decisions, remains largely unexplored. Here, we show that transient UPR^mt activation occurs during somatic reprogramming in mouse embryonic fibroblasts. We observe a c-Myc-dependent, transient decrease in mitochondrial proteolysis, accompanied by UPR^mt activation at the early phase of pluripotency acquisition. UPR^mt impedes the mesenchymal-to-epithelial transition (MET) through c-Jun, thereby inhibiting pluripotency acquisition. Mechanistically, c-Jun enhances the expression of acetyl-CoA metabolic enzymes and reduces acetyl-CoA levels, thereby affecting levels of H3K9Ac, linking mitochondrial signalling to the epigenetic state of the cell and cell fate decisions. c-Jun also decreases the occupancy of H3K9Ac at MET genes, further inhibiting MET. Our findings reveal the crucial role of mitochondrial UPR-modulated MET in pluripotent stem cell plasticity. Additionally, we demonstrate that the UPR^mt promotes cancer cell migration and invasion by enhancing epithelial-to-mesenchymal transition (EMT). Given the crucial role of EMT in tumour metastasis^3,4, our findings on the connection between the UPR^mt and EMT have important pathological implications and reveal potential targets for tumour treatment.

The balance between mitochondrial calcium (_mCa²⁺) uptake and efflux is essential for ATP production and cellular homeostasis. The mitochondrial sodium-calcium exchanger, NCLX, is a critical route of _mCa²⁺ efflux in excitable tissues, such as the heart and brain, and animal models support NCLX as a promising therapeutic target to limit pathogenic _mCa²⁺ overload. However, the mechanisms that regulate NCLX activity are largely unknown. Using proximity biotinylation proteomic screening, we identify the mitochondrial inner membrane protein TMEM65 as an NCLX binding partner that enhances sodium (Na⁺)-dependent _mCa²⁺ efflux. Mechanistically, acute pharmacological NCLX inhibition or genetic deletion of NCLX ablates the TMEM65-dependent increase in _mCa²⁺ efflux, and loss-of-function studies show that TMEM65 is required for Na⁺-dependent _mCa²⁺ efflux. In line with these findings, knockdown of Tmem65 in mice promotes _mCa²⁺ overload in the heart and skeletal muscle and impairs both cardiac and neuromuscular function. Collectively, our results show that loss of TMEM65 function in excitable tissue disrupts NCLX-dependent _mCa²⁺ efflux, causing pathogenic _mCa²⁺ overload, cell death, and organ-level dysfunction. These findings demonstrate the essential role of TMEM65 in regulating NCLX-dependent _mCa²⁺ efflux and suggest modulation of TMEM65 as a therapeutic strategy for a variety of diseases.

Environmental thermal stress substantially affects cellular plasticity of thermogenic adipocytes and energy balance through transcriptional and epigenetic mechanisms in rodents. However, roles of cold-adaptive epigenetic regulation of brown adipose tissue (BAT) in systemic energy metabolism in humans remained poorly understood. Here we report that individuals whose mothers conceived during cold seasons exhibit higher BAT activity, adaptive thermogenesis, increased daily total energy expenditure and lower body mass index and visceral fat accumulation. Structural equation modelling indicated that conception during the cold season protects against age-associated increase in body mass index through BAT activation in offspring. Meteorological analysis revealed that lower outdoor temperatures and greater fluctuations in daily temperatures during the fertilization period are key determinants of BAT activity. These findings suggest that BAT metabolic fate and susceptibility of metabolic diseases are preprogrammed by the epigenetic inheritance of cold exposure before the fertilization in humans.