Yu-Hua Tseng

Anatomic location of white adipose tissue is a determinant of cardiometabolic risk. To understand differences within/between adipose depots, we generated 65,668 single-nucleus transcriptomes from human subcutaneous or intraabdominal adipose tissue (SAT/IAT). Unsupervised analysis reveals 26 adipose-resident cell clusters including two subpopulations of mature adipocytes, characterized by high vs. low expression of adipocyte maturation genes (ADIPOMAT^hi vs. ADIPOMAT^lo). ADIPOMAT^lo adipocytes demonstrate a low-differentiation, pro-inflammatory, and pro-fibrotic transcriptome. IAT-resident ADIPOMAT^lo were more abundant in higher BMI donors, while SAT-resident ADIPOMAT^lo associated with impaired glycemia. TSHZ3 is identified as a candidate regulator of ADIPOMAT^lo transcriptome. TSHZ3 knockdown in adipogenic progenitors inhibits differentiation, with downregulation of early adipogenic regulators (e.g., CEBPA/B, PPARG) and mature adipocyte genes. Heterozygous deletion of Tshz3 in mice reduces SAT and IAT weight. Here, we show that adipocyte subsets with distinct transcriptomic signature reside in human WAT; altered TSHZ3-mediated transcriptional regulation may contribute to low-maturation subpopulation linked to metabolic disease.

Adipose tissue has emerged as a dynamic endocrine organ that coordinates systemic energy balance and cardiometabolic health. This Review highlights the dual humoral and neuronal pathways through which adipose tissue regulates systemic metabolism. Humoral signals include peptide hormones, lipid mediators, metabolites, chemokines and exosomal microRNAs secreted by adipose depots. Neuronal circuits control adipose function rapidly and precisely: sympathetic efferents trigger lipolysis in white adipose tissue and thermogenesis in brown adipose tissue, whereas sensory afferents detect chemical, thermal and mechanical signals to adjust sympathetic activity. Nutritional and environmental stimuli (for example, diet, cold exposure and exercise), along with pathological states (for example, obesity, type 2 diabetes mellitus, lipodystrophy and ageing-associated disorders), dynamically modulate these endocrine and neural outputs. Methodological innovations, such as omics based on mass spectrometry or liquid chromatography-mass spectrometry, secretome labelling, adipose tissue organoid models and click chemistry, enable high-resolution characterization of adipose-derived signals and their targets. Finally, we discuss translational opportunities, including synthetic analogues of lipophilic hormones, and future therapeutic strategies that harness adipose communication networks.

Three-dimensional genome organization underlies gene regulation, yet how acute hormonal signalling reshapes chromatin structure to control metabolism remains unclear. β3-adrenergic receptor (β3-AR) hormonal signalling drives adipocyte thermogenesis. Here, we show three-dimensional genome maps of mouse and primary human brown adipocytes during thermogenesis using Micro-C. We find that β3-AR signalling rapidly reorganizes chromatin loops within 4 h, with dynamically gained loops coupled to thermogenic gene activation in both species. Mechanistically, β3-AR stimulation promotes histone variant H2A.Z deposition to enhance chromatin accessibility at loop anchors, facilitating the recruitment of bridging factor MED1. Loss of H2A.Z compromises loop formation and thermogenic gene activation across species. Brown fat-specific H2A.Z deficiency in mice impairs thermogenic activity and glucose tolerance. Integration with genome-wide association studies links H2A.Z-occupied loops to genetic variants associated with obesity and related metabolic disorders. Together, our findings uncover a cross-species conserved β3-AR signalling–H2A.Z axis that rapidly reorganizes chromatin interactions in adipocyte thermogenesis, providing mechanistic and translational insights into metabolic regulation.

While cold exposure drives lipid flux from adipose tissue to the liver, this enhanced inter-organ crosstalk does not result in sustained hepatic steatosis during prolonged acclimation, indicating that factors beyond lipid flux shape metabolic outcome. To interrogate this adaptation, we performed integrated lipidomic and metabolic profiling across tissues and circulating lipoproteins over the course of cold acclimation. We showed that cold acclimation induces systemic reprogramming of lipid quality in mice, characterized by enrichment of n-3 highly unsaturated fatty acids (HUFAs) as a consequence of upregulation of fatty acid desaturases (FADS1 and 2) in the liver and white adipose tissue, thus increasing hepatic n-3/n-6 ratio. Cold-induced increase in n-3 HUFAs cause the suppression of SCD1-mediated desaturation, thus yielding a depletion of monounsaturated fatty acids (MUFAs) in the liver, along with the suppression of lipogenic markers. Notably, this high-HUFA/low-MUFA lipid signature is present in both hepatic free fatty acid and triglyceride pools, indicating that lipid remodeling occurs upstream of triglyceride synthesis. Lipidomic analysis revealed that the remodeled triglycerides are incorporated into very-low-density and intermediate density lipoproteins (VLDL and IDL), thereby propagating hepatic lipid reprogramming to the circulation. Thus, by selectively increasing endogenous n-3 HUFA availability, cold adaptation suppresses hepatic DNL and MUFA-driven triglyceride assembly, buffering lipid accumulation despite sustained fatty acid influx and reshaping systemic lipid distribution with potential cardiometabolic impact.

Adipocytes exist along a functional spectrum: white adipocytes are energy storing, and brown adipocytes have thermogenic capacity such that activation may counteract obesity-related disease. In between are UCP1-expressing beige adipocytes, which can transition between these two energetic states. We previously showed that bone morphogenetic protein 7 (BMP7), a member of the TGF-β superfamily, enables differentiation of brown preadipocytes to mature thermogenic cells. To see whether immortalized, clonal human white and brown preadipocytes (hWAs and hBAs, respectively) would become more thermogenic in response to BMP exposure, we treated them with BMP7 or BMP4 for the first 7 days of a 30-day differentiation protocol. In hBAs, absence of either BMP7 or BMP4 led to lower expression of brown-specific markers and oxygen consumption relative to 7 days with either BMP. hWAs treated for 7 days with either BMP did not increase expression of thermogenic protein UCP1 nor induce a brown-like transcription profile. However, BMP-treated hWAs produced adipocytes that had higher basal and drug-induced maximal oxygen consumption, which was UCP1-independent and due substantially to the futile creatine cycle. Our results demonstrate that energetically quiescent hWAs can be pushed into an energy-expending phenotype without transdifferentiation into beige adipocytes, providing a new approach to treat obesity-related metabolic disease.

Brown adipose tissue (BAT) plays a key role in non-shivering thermogenesis and is a promising target for enhancing energy expenditure to combat obesity. Soluble epoxide hydrolase (sEH) is a cytosolic enzyme that catalyzes the conversion of epoxy fatty acids into less active diols. We have reported that local administration of the sEH inhibitor, t-TUCB, to the endogenous interscapular BAT (iBAT) of diet-induced obese mice decreased serum triglycerides and enhanced the expression of essential genes associated with lipid metabolism. Here, the effects of sEH inhibition by t-AUCB were assessed on human brown adipocyte (HuBr) differentiation and in nude mice transplanted with t-AUCB-treated HuBr. HuBr cells were differentiated with t-AUCB (1–10 µM) or the vehicle (0.1% DMSO). HuBr differentiated with t-AUCB at 5 μM (AUCB 5) or DMSO was mixed with matrix gel and transplanted into the nude mice. The mice were then fed a high-fat diet for eight weeks. The mice receiving AUCB 5-treated HuBr exhibited markedly reduced lipid accumulation in the iBAT compared with DMSO or matrix-only controls, along with increased protein expression of thermogenic PGC1α and UCP1, fatty acid transporter CD36, and CPT1A in the iBAT, while the NFκB inflammatory pathways were suppressed in both the AUCB 5 and DMSO groups. Moreover, the PGC1α and CPT1A protein levels were elevated, and the adipocyte sizes were decreased in the epididymal white adipose tissue of the AUCB 5 group. Our findings indicate that the transplantation of HuBr treated with AUCB 5 may stimulate thermogenesis, enhance lipid metabolism, and reduce inflammation in iBAT.

Introduction: Aerobic exercise and cold exposure modulate lipid mediator production, which may optimize physiological resilience. The Yukon Arctic Ultra (YAU), a 692-km self-provisioned multiday endurance event, offers a unique opportunity to examine lipidomic adaptations to nutrients and environmental and physical stress. This study aimed to identify lipid mediators responsive in YAU athletes compared to control participants. Methods: Nine athletes and six controls were recruited from the 2017 and 2019 YAU events. Targeted liquid chromatography-tandem mass spectrometry/mass spectrometry-based signaling lipidomic analysis was conducted on serum samples collected from participants at pre-event, during the event, and post-event time points. Results: Athletes and controls did not differ significantly in age, body mass index (BMI), fat mass index (FMI), or fat-free mass index. During the event, athletes exhibited significant reductions in BMI, fat mass, and FMI, whereas no changes were observed in controls. Athletes showed higher baseline levels of anti-inflammatory oxylipins, including resolvin D2 and lipoxin A4 (LXA4), and lower levels of the pro-inflammatory leukotriene E4 compared to controls. Linoleic acid- and α-linolenic acid-derived oxylipins were also elevated in athletes. Notably, these anti-inflammatory lipids remained elevated throughout the event. Certain hydroxy-eicosapentaenoic acids demonstrated a declining trend during the event in athletes. Discussion: YAU athletes exhibit a distinct lipidomic signature marked by persistently elevated anti-inflammatory oxylipins, likely reflecting a complex interplay between adipose tissue and skeletal muscle. Overall, the oxylipin shifts point to anti-inflammatory and thermogenic adaptations that support physiological resilience during physical, nutrient, and environmental stress in austere circumstances.

Thermogenic adipose tissues, including brown and beige, exhibit remarkable cellular and metabolic adaptations to environmental and physiological cues, contributing to improved metabolic health. Among these adaptations, adipose progenitor cells (APCs), a heterogeneous cell population comprising distinct subsets, play a crucial role in generating thermogenic adipocytes and promoting healthy adipose tissue remodeling and metabolic homeostasis. Therefore, targeting APCs offers a potential therapeutic approach for regulating adipose plasticity and remodeling to address metabolic dysregulation. The precise identity of APCs and the roles of specific APC subtypes in metabolic regulation and diseases remain to be elucidated. Here, we summarize recent findings on the lineage of APCs that give rise to thermogenic adipocytes and how environmental conditions regulate their proliferation and differentiation. Finally, we discuss the potential of targeting APCs as an alternative therapeutic strategy to combat metabolic diseases.

Introduction: Brown adipose tissue (BAT) contributes to thermogenesis and has been proposed as a therapeutic target for metabolic disease. Thyroid hormones (THs) regulate thermogenic activity, but the relationship between circulating and local TH concentrations and their associations with thermogenic gene and pathway expression in human adipose tissue remain unclear. Methods: We obtained paired deep neck and subcutaneous adipose tissue samples from adults undergoing thyroid surgery, which represent BAT and white adipose tissue, respectively. Serum and local adipose tissue TH concentrations (T3, T4, TSH) were measured. Bulk RNA-sequencing was performed on adipose tissue samples. Associations between hormone concentrations and thermogenic gene expression and pathway activation were analyzed, with false discovery rate correction for multiple testing. Results: Both serum and local T4 concentrations were positively associated with thermogenic pathway activation in deep neck adipose tissue. Although serum T3 was also positively associated, local T3 was inversely associated with thermogenic pathways in deep neck adipose tissue. However, circulating TH concentrations did not correlate with local tissue hormone levels. No significant associations were observed between serum or local TH concentrations and individual thermogenic gene expression after correction for different clinical covariates and multiple comparisons. Conclusion: Local regulation of THs may play a role in human adipose tissue thermogenic activity. Pathway-level transcriptomic analysis may better capture these effects than single-gene approaches. Deep neck adipose tissue can serve as a practical model for studying BAT function and endocrine regulation in humans.