Cell metabolism最新文献

Adipocytes as vital energy reservoirs respond to systemic metabolic demands by storing or releasing lipids. Whether they can promote tissue regeneration through local metabolic communication remains unclear. We found that after skin injury, macrophages quickly infiltrate dermal adipose tissue, where they promote free fatty acid release from adipocytes via serum amyloid A3-dependent lipolysis, which, in turn, promotes hair regrowth. Epithelial hair follicle stem cells (eHFSCs) absorb the released monounsaturated fatty acids via fatty acid translocase CD36 and activate the transcriptional coactivator Pgc1-α. Downstream of Pgc1-α, increased fatty acid oxidation and mitochondrial biogenesis enhance energy production, enabling eHFSCs to exit quiescence. Topical treatment of monounsaturated fatty acids suffices to promote hair growth by activating eHFSCs. Our findings demonstrate a macrophage-to-adipocyte-to-hair follicle axis that promotes tissue-level regeneration via short-range metabolic signaling through free fatty acids. Analogous regeneration-facilitating mechanisms elicited by injury-induced panniculitis may operate in other adipose-rich organs.

In adipocytes, hormone-sensitive lipase (HSL) plays a key role in hydrolyzing triacylglycerols that are stored in lipid droplets. Contrary to the expected phenotype, HSL-deficient mice and humans exhibit lipodystrophy. Here, we show that HSL is also present in the adipocyte nucleus. Mouse models with different HSL subcellular localizations reveal that nuclear HSL is essential for the maintenance of adipose tissue. Gene silencing in human adipocytes shows that HSL, independently of its enzymatic activity, exerts opposing effects on mitochondrial oxidative phosphorylation and the extracellular matrix. Mechanistically, we found that HSL accumulates in the nucleus by interacting with the transforming growth factor β (TGF-β) signaling mediator, mothers against decapentaplegic homolog 3 (SMAD3). Conversely, HSL phosphorylation induces nuclear export. In vivo, HSL accumulates in the nucleus of adipocytes during high-fat feeding with the converse effect during fasting. Together, our data show that as both a cytosolic enzyme and a nuclear factor, HSL plays a pivotal role in adipocyte biology and adipose tissue maintenance.

Tumor-initiating cells (TICs) preferentially reside in poorly vascularized, nutrient-stressed tumor regions, yet how they adapt to glucose limitation is unclear. We show that lung TICs, unlike bulk tumor cells, can switch from glucose to ketone utilization under glucose deprivation. Ex vivo ketone supplementation or a prolonged ketogenic diet supports TIC growth and tumor-initiating capacity. Integrated metabolomics, genomics, and flux analyses reveal that ketones fuel ketolysis, fatty acid synthesis, and de novo lipogenesis. Paradoxically, ketogenic diet intervention creates metabolic vulnerabilities in TICs, sensitizing them toward inhibition of the ketone transporter monocarboxylate transporter 1 (MCT1), regulated by its chaperone protein CD147, as well as toward pharmacological blockade of fatty acid synthase (FASN). Loss of CD147 ablates TICs under glucose limitation conditions in vitro and in vivo. These findings uncover a nutrient-responsive metabolic switch in lung TICs and provide mechanistic insight into how dietary manipulation can influence cancer progression and enhance the efficacy of targeted therapies.

The rise in the prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is attributed significantly to dysregulated lipid metabolism. This study discovered that the enedioic acid ATP-citrate lyase (ACLY) inhibitor 326E, an investigational new drug in a phase 2a study for hypercholesterolemia, markedly reduces hepatic lipid accumulation and alleviates MASH in mouse models of MASH. Mechanistic studies demonstrated that 326E exerts these effects not only by inhibiting ACLY to reduce de novo lipogenesis (DNL) but also as a peroxisome proliferator-activated receptor α (PPARα) allosteric regulator to increase hepatic fatty acid oxidation (FAO). The efficacy of activated PPARα for MASH is enhanced by suppressed recycling of FAO products to lipid accumulation as a result of ACLY inhibition. Subsequent studies in cynomolgus monkeys (Macaca fascicularis) confirmed the effectiveness of 326E for MASH in primate species. In a randomized phase 1b/2a clinical trial in patients with MASH (NCT06491576), 326E was well tolerated and reduced circulating gamma-glutamyl transferase (γ-GGT). Taken together, our results indicate the therapeutic potential of 326E for MASH via distinctive dual mechanisms of inhibiting ACLY while activating PPARα.

Since the industrial revolution, human dietary habits have invariably trended toward dietary urbanization, during which the human gut microbiota has rapidly changed. However, the human genome cannot change substantially over one generation, leaving it potentially ill-equipped to adapt to evolving microbial functions associated with rising non-communicable diseases (NCDs). In this review, we map the chronological alterations in dietary patterns and incidences of NCDs during global urbanization while emphasizing the gut microbiome as the centerpiece. We then illustrate losses and acquisitions of gut microbes during worldwide urbanization and delineate the mechanisms by which urbanized diets may disrupt host-microbiome interactions, linking to the onset of NCDs. Building on this, we further propose a microbiome-directed precision-nutrition framework that integrates both inter-population and intra-population variations to promote diet-fueled host-microbiome synergism and hence to counteract urbanization-associated diseases. These insights will instruct future microbiome-targeted diets to thwart NCDs.

Metabolic homeostasis is maintained by redundant pathways to ensure adequate nutrient supply during fasting and other stresses. These pathways are regulated locally in tissues and systemically via the liver, kidney, and circulation. Here, we characterize how serine, glycine, and one-carbon (SGOC) metabolism fluxes across the eye, liver, and kidney sustain retinal amino acid levels and function. Individuals with macular telangiectasia (MacTel), an age-related retinal disease with reduced circulating serine and glycine, carrying deleterious alleles in SGOC metabolic enzymes exhibit an exaggerated reduction in circulating serine. A Phgdh^+/- mouse model of this haploinsufficiency experiences accelerated retinal defects upon dietary serine/glycine restriction, highlighting how otherwise silent haploinsufficiencies can impact retinal health. We demonstrate that serine-associated retinopathy and peripheral neuropathy are reversible, as both are restored in mice upon serine supplementation. These data provide molecular insights into the genetic and metabolic drivers of neuro-retinal dysfunction while highlighting therapeutic opportunities to ameliorate this pathogenesis.

Obesity has been implicated in the rise of autoimmunity in women. We report that obesity induces a serum protein signature that is associated with T helper 1 (Th1), interleukin (IL)-17, and multiple sclerosis (MS) signaling pathways selectively in human females. Females, but not male mice, subjected to diet-induced overweightness/obesity (DIO) exhibited upregulated Th1/IL-17 inflammation in the central nervous system during experimental autoimmune encephalomyelitis, a model of MS. This was associated with worsened disability and a heightened expansion of myelin-specific Th1 cells in the peripheral lymphoid organs. Moreover, at steady state, DIO increased serum levels of interferon (IFN)-α and potentiated STAT1 expression and IFN-γ production by naive CD4⁺ T cells uniquely in female mice. This T cell phenotype was driven by increased adiposity and was prevented by the removal of ovaries or knockdown of the type I IFN receptor in T cells. Our findings offer a mechanistic explanation of how obesity enhances autoimmunity.

To examine the roles of mitochondrial calcium Ca²⁺ ([Ca²⁺]_mt) and cytosolic Ca²⁺ ([Ca²⁺]_cyt) in the regulation of hepatic mitochondrial fat oxidation, we studied a liver-specific mitochondrial calcium uniporter knockout (MCU KO) mouse model with reduced [Ca²⁺]_mt and increased [Ca²⁺]_cyt content. Despite decreased [Ca²⁺]_mt, deletion of hepatic MCU increased rates of isocitrate dehydrogenase flux, α-ketoglutarate dehydrogenase flux, and succinate dehydrogenase flux in vivo. Rates of [¹⁴C₁₆]palmitate oxidation and intrahepatic lipolysis were increased in MCU KO liver slices, which led to decreased hepatic triacylglycerol content. These effects were recapitulated with activation of CAMKII and abrogated with CAMKII knockdown, demonstrating that [Ca²⁺]_cyt activation of CAMKII may be the primary mechanism by which MCU deletion promotes increased hepatic mitochondrial oxidation. Together, these data demonstrate that hepatic mitochondrial oxidation can be dissociated from [Ca²⁺]_mt and reveal a key role for [Ca²⁺]_cyt in the regulation of hepatic fat mitochondrial oxidation, intrahepatic lipolysis, gluconeogenesis, and lipid accumulation.

Sleep is essential for overall health, and its disruption is linked to increased risks of metabolic, cognitive, and cardiovascular dysfunctions; however, the molecular mechanisms remain poorly understood. This study investigated how sleep disturbances contribute to metabolic imbalance and cognition impairment using a chronic sleep fragmentation (SF) mouse model. SF mice exhibited impaired cognition, glucose metabolism, and insulin sensitivity compared with controls. We identified increased acetate levels in hypothalamic astrocytes as a defensive response in SF mice. Through acetate infusion or astrocyte-specific Acss1 deletion to elevate acetate levels, we observed mitigated metabolic and cognitive impairments in SF mice. Mechanistically, acetate binds and activates pyruvate carboxylase, thereby restoring glycolysis and the tricarboxylic acid cycle. Among individuals most commonly affected by SF, patients with obstructive sleep apnea exhibited elevated acetate levels when coupled with type 2 diabetes. Our study uncovers the protective effect of acetate against sleep-induced metabolic and cognitive impairments.

The intestine constantly encounters and adapts to the external environment shaped by diverse dietary nutrients. However, whether and how gut adaptability to dietary challenges is compromised in ulcerative colitis is incompletely understood. Here, we show that a transient high-fat diet exacerbates colitis owing to inflammation-compromised bile acid tolerance. Mechanistically, excessive tumor necrosis factor (TNF) produced at the onset of colitis interferes with bile-acid detoxification through the receptor-interacting serine/threonine-protein kinase 1/extracellular signal-regulated kinase pathway in intestinal epithelial cells, leading to bile acid overload in the endoplasmic reticulum and consequent apoptosis. In line with the synergy of bile acids and TNF in promoting gut epithelial damage, high intestinal bile acids correlate with poor infliximab response, and bile acid clearance improves infliximab efficacy in experimental colitis. This study identifies bile acids as an "opportunistic pathogenic factor" in the gut that would represent a promising target and stratification criterion for ulcerative colitis prevention/therapy.