Qiong Annabel Wang

Brown adipocytes (BAs) are thermogenic cells that regulate energy homeostasis, and age-related declines in thermogenesis contribute to cold sensitivity ^1–5 . We previously identified a BA subpopulation with low UCP1 expression (hereafter, BA-L cells) that coexists with the classical, high-UCP1-expressing BAs (hereafter, BA-H cells) ⁶ . Here we show that IL-1β secreted by neutrophils and macrophages stabilizes nearby BAs in the BA-L state. Specifically, IL-1β stabilizes hexose-6-phosphate dehydrogenase (H6PD) protein from degradation to ensure the generation of active glucocorticoids, which activate the glucocorticoid receptor (GR, encoded by Nr3c1 ) and increase the expression of its target gene, regulator of G-protein signalling 2 ( Rgs2 ), thereby suppressing UCP1 expression. Cold exposure reduces IL-1β levels, depending on sympathetic innervation, leading to H6PD degradation and the conversion of BA-L cells to BA-H cells, thereby enhancing UCP1-dependent thermogenesis. Rising environmental temperatures trigger the opposite events. BA-specific inducible deletion of Nr3c1 during cold exposure locks these cells in the BA-H state, leading to persistent thermogenesis and increased energy expenditure days after the mice return to room temperature. Notably, IL-1β is elevated in aged brown adipose tissue, resulting in a locked low BA-H/BA-L ratio and cold intolerance. Suppressing GR in aged mice restores the BA-H/BA-L ratio, resumes thermogenesis and increases energy expenditure. Our findings reveal a spatiotemporal neuronal–immune regulation of BA heterogeneity that governs thermogenesis and offers a fundamental understanding of the mechanisms underlying increased cold sensitivity in older individuals.

Sebaceous glands (SGs) are essential for maintaining skin homeostasis and barrier function. However, the cell biology and lineage of SGs remain poorly understood in vivo. Here we performed bulk isolation of murine SGs, uncovered their molecular features, and generated SG-specific tool mouse models. Tracing with SG-Chaser mice revealed SG heterogeneity and their dynamic and distinct responses to common external stimuli. Specifically, some SG stem cell (SGSC) descendants homed back to the bulge and underwent redifferentiation, the toggling of which is critical for preserving stem cell pool and maintaining SG homeostasis. Combining single-cell RNA sequencing with lineage tracing, we identified the origin of murine SGs and found that Krt15 + cells gave rise to both typical and atypical SGs via divergent differentiation trajectories. As lipid-rich cells, murine sebocytes exhibit a differentiation program closely resembling that of adipocytes and highly reliant on Pparγ. Topical pharmacological regulation of Pparγ can effectively modulate sebocytes homeostasis in both mice and humans. Together, these results unveil the multilayered dynamics of murine SGs and suggest viable approaches to modulate SG homeostasis and maintain barrier integrity.

Adipose tissue, a pivotal player in whole-body energy homeostasis and insulin sensitivity, undergoes considerable remodelling throughout the ageing process, a facet that has garnered little attention until the past decade. This Review comprehensively summarizes the dynamic metabolic, cellular and functional changes that occur in white and thermogenic adipose tissue during distinct ageing stages, across different adipose tissue depots. We emphasize the influence of ageing on different cell types within adipose tissue, including adipocytes, adipocyte progenitors, immune cells and senescent cells, and their collective effect on adipose tissue function and systemic metabolism. We also decipher the correlation between adipose tissue ageing and prevalent age-related conditions such as metabolic dysfunction-associated fatty liver disease and cardiovascular diseases. Finally, the Review delves into the potential of current anti-ageing interventions to beneficially affect adipose tissue, encompassing caloric restriction, metformin, glucagon-like peptide 1 receptor agonists and senolytics. The discussion extends to the exploration of whether targeting adipose tissue through such interventions could emerge as a prominent therapeutic strategy for mitigating age-related diseases and enhancing the healthspan and lifespan of the ageing population.

Starting at middle age, adults often suffer from visceral adiposity and associated adverse metabolic disorders. Lineage tracing in mice revealed that adipose progenitor cells (APCs) in visceral fat undergo extensive adipogenesis during middle age. Thus, despite the low turnover rate of adipocytes in young adults, adipogenesis is unlocked during middle age. Transplantations quantitatively showed that APCs in middle-aged mice exhibited high adipogenic capacity cell-autonomously. Single-cell RNA sequencing identified a distinct APC population, the committed preadipocyte, age-enriched (CP-A), emerging at this age. CP-As demonstrated elevated proliferation and adipogenesis activity. Pharmacological and genetic manipulations indicated that leukemia inhibitory factor receptor signaling was indispensable for CP-A adipogenesis and visceral fat expansion. These findings uncover a fundamental mechanism of age-dependent adipose remodeling, offering critical insights into age-related metabolic diseases.

Adipose tissue beiging refers to the process by which beige adipocytes emerge in classical white adipose tissue depots. Beige adipocytes dissipate chemical energy and secrete adipokines, such as classical brown adipocytes, to improve systemic metabolism, which is beneficial for people with obesity and metabolic diseases. Cold exposure and β3-adrenergic receptor (AR) agonist treatment are two commonly used stimuli for increasing beige adipocytes in mice; however, their underlying biological processes are different. Transcriptional analysis of inguinal white adipose tissue (iWAT) has revealed that changes in extracellular matrix (ECM) pathway genes are specific to cold exposure. Hyaluronic acid (HA), a non-sulfated linear polysaccharide produced by nearly all cells, is one of the most common components of ECM. We found that cold exposure significantly increased iWAT HA levels, whereas the β3-AR agonist CL316,243 did not. Increasing HA levels in iWAT by Has2 overexpression significantly increases cold-induced adipose tissue beiging; in contrast, decreasing HA by Spam1 overexpression, which encodes a hyaluronidase that digests HA, significantly decreases cold-induced iWAT beiging. All these data implicate a role of HA in promoting adipose tissue beiging, which is unique to cold exposure. Given the failure of β3-AR agonists in clinical trials for obesity and metabolic diseases, increasing HA could serve as a new approach for recruiting more beige adipocytes to combat metabolic diseases.

Upon endoplasmic reticulum (ER) stress, activation of the ER-resident transmembrane protein kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1) initiates a key branch of the unfolded protein response (UPR) through unconventional splicing generation of the transcription factor X-box-binding protein 1 (XBP1s). Activated IRE1 can form large clusters/foci, whose exact dynamic architectures and functional properties remain largely elusive. Here we report that, in mammalian cells, formation of IRE1α clusters is an ER membrane-bound phase separation event that is coupled to the assembly of stress granules (SGs). In response to different stressors, IRE1α clusters are dynamically tethered to SGs at the ER. The cytosolic linker portion of IRE1α possesses intrinsically disordered regions and is essential for its condensation with SGs. Furthermore, disruption of SG assembly abolishes IRE1α clustering and compromises XBP1 mRNA splicing, and such IRE1α–SG coalescence engenders enrichment of the biochemical components of the pro-survival IRE1α–XBP1 pathway during ER stress. Our findings unravel a phase transition mechanism for the spatiotemporal assembly of IRE1α–SG condensates to establish a more efficient IRE1α machinery, thus enabling higher stress-handling capacity.

The coexistence of brown adipocytes with low and high thermogenic activity is a fundamental feature of brown adipose tissue heterogeneity and plasticity. However, the mechanisms that govern thermogenic adipocyte heterogeneity and its significance in obesity and metabolic disease remain poorly understood. Here we show that in male mice, a population of transcription factor jun-B (JunB)-enriched (JunB⁺) adipocytes within the brown adipose tissue exhibits lower thermogenic capacity compared to high-thermogenic adipocytes. The JunB⁺ adipocyte population expands in obesity. Depletion of JunB in adipocytes increases the fraction of adipocytes exhibiting high thermogenic capacity, leading to enhanced basal and cold-induced energy expenditure and protection against diet-induced obesity and insulin resistance. Mechanistically, JunB antagonizes the stimulatory effects of PPARγ coactivator-1α on high-thermogenic adipocyte formation by directly binding to the promoter of oestrogen-related receptor alpha, a PPARγ coactivator-1α downstream effector. Taken together, our study uncovers that JunB shapes thermogenic adipocyte heterogeneity, serving a critical role in maintaining systemic metabolic health.

The production of beige adipocytes following cold exposure is blocked as mice get older and leads to changes in the expression of metabolic genes.

Summary: Fatty acid synthase (FASN) maintains de novo lipogenesis (DNL) to support rapid growth in most proliferating cancer cells. Lipogenic acetyl-CoA is primarily produced from carbohydrates but can arise from glutamine-dependent reductive carboxylation under hypoxia. Here we show that reductive carboxylation also occurs in the absence of DNL in cells with defective FASN. In this state, reductive carboxylation was mainly catalyzed by isocitrate dehydrogenase-1 (IDH1) in the cytosol, but IDH1-generated citrate was not used for DNL. Metabolic flux analysis (MFA) revealed that FASN-deficiency induced a net cytosol-to-mitochondria citrate flux through citrate transport protein (CTP). A similar pathway was previously shown to mitigate detachment-induced mitochondrial reactive oxygen species (mtROS) in anchorage-independent tumor spheroids. We further demonstrate that FASN-deficient cells acquire resistance to oxidative stress in a CTP- and IDH1-dependent manner. Together with the reduced FASN activity in tumor spheroids, these data indicate that anchorage-independent malignant cells trade FASN-supported rapid growth for a cytosol-to-mitochondria citrate flux to gain redox capacity against detachment-induced oxidative stress.