Open research questions in Adipose Tissue and Metabolism

What the literature leaves open

• The current body of evidence positions adipose tissue browning as a central modifier of metabolic homeostasis and a compelling upstream target in MASLD. Mechanistically, browning reprograms white adipose tissue into a thermogenically active phenotype that enhances mitochondrial β-oxidation, increases energy expenditure, and reduces circulating free fatty acids, thereby limiting hepatic lipid accumulation. Beyond substrate redistribution, browning exerts systemic effects through endocrine signaling, with batokines such as FGF21, irisin, and Nrg4 modulating hepatic lipid metabolism, insulin sensitivity, and inflammatory pathways. These interconnected processes highlight a tightly regulated adipose–liver axis that influences disease progression across the MASLD spectrum. Preclinical models consistently demonstrate improvements in steatosis, inflammation, and fibrosis; while emerging human studies suggest favorable associations with metabolic health. 1 3Current Obesity Reports(2026)15:68 However, variability in brown adipose tissue activity, limited durability of induced browning, and heterogeneity in human responses underscore the complexity of translating these findings into clinical benefit. Despite this strong mechanistic rationale, several key factors limit the clinical translation of adipose browning in human MASLD. In adult humans, BAT mass and thermogenic capacity are relatively low, highly variable, and further diminished in obesity and advanced metabolic disease. These features substantially restrict the maximal metabolic impact that can be achieved through browning-based interventions. Moreover, current approaches to stimulate browning—such as cold exposure, β3-adrenergic agonists, and metabolic signaling molecules—often produce modest or short-lived effects and may be associated with limited tolerability or off-target consequences. Consequently, while adipose browning can favorably influence lipid flux, insulin sensitivity, and inflammatory pathways, its overall contribution to clinically meaningful improvements in MASLD is likely to be incremental rather than transformative when applied in isolation. Collectively, adipose browning is best positioned as an upstream metabolic modulator that may enhance the efficacy of broader therapeutic strategies, including lifestyle interventions and pharmacologic treatments, rather than serving as a standalone approach. In addition, the interspecies differences in thermogenic capacity and responsiveness further explain the gap between preclinical efficacy and clinical outcomes, underscoring the need for realistic expectations when translating browningbased interventions to human MASLD. Moving forward, research must shift toward bridging mechanistic insights with clinically meaningful outcomes.

  Adipose Tissue Browning in MASLD and Its Molecular Mechanisms and Metabolic Crosstalk · 2026 · DOI

• BACKGROUND: Tannic acid (TA) is a hydrolysable plant secondary metabolite known to influence multiple physiological processes in animals; however, its role in regulating brown adipose tissue (BAT) thermogenesis remains poorly understood.

  Transcriptome analysis of brown adipose tissue in Brandt’s vole treated with tannic acid under cold exposure · 2026 · DOI

• Additional age-related physi- ological changes—such as alterations in SNS activity and gastric emptying—may also contribute to this variability, but these factors have not been systematically examined alongside DIT in comparative studies of young and older adults (Fig.

  Does Aging Affect Diet-Induced Thermogenesis? Revisiting the Evidence from Human Studies · 2026 · DOI

• However, because its effects are influenced by treatment duration, dose, and {beta}-adrenergic receptor responsiveness, it remains unclear how extended intermittent CB exposure alters the skeletal muscle proteome.

  Repeated intermittent clenbuterol administration induces exposure history-dependent proteomic remodeling in mouse skeletal muscle · 2026 · DOI

• However, our understanding of how ACL supports cardiac metabolic adaptation and its potential to modulate disease pathophysiology has not yet been investigated.

  Loss of ATP-Dependent Citrate Lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling · 2026 · DOI

• While emerging evidence suggests that PLLA modulates the differentiation and lipolysis of dermal adipocytes, its role in autologous fat transplantation remains unclear.

  PLLA Microspheres Regulate Adipocyte Dedifferentiation via Lactate: A Novel Strategy for Fat Graft Survival Enhancement · 2026 · DOI

• Together, these results provide new molecular insight into the metabolic basis of chemotherapy-induced muscle wasting and support further investigation of NAD+-targeted strategies in this context.

  Chemotherapy induces tissue NAD+ loss, and downregulation of NAD+ biosynthetic enzyme Nrk2 marks muscle wasting · 2026 · DOI

• High-intensity interval training (HIIT) is a time-efficient exercise strategy with potent anti-inflammatory and metabolic benefits; however, its effects on adipose tissue inflammatory signaling and microRNA (miRNA) regulation remain incompletely understood.

  High-Intensity Interval Training Remodels Adipose Tissue Inflammatory Signaling and Enhances Immunometabolic Health via microRNA Regulation · 2026 · DOI

• Furthermore, the relationship between the observed optical parameters and clinically rel- evant outcomes remains to be established. The findings support further investigation of optical methods as potential complementary tools for experimental monitoring of T1DM tissue alterations, par- ticularly those related to hydration status.

  Modulation of optical properties of adipose tissue in diabetes mellitus associated with its glycation and hydration · 2026 · DOI

• Recently, we observed a remarkable decrease in serum irisin levels in patients with AA, as well as beneficial effects of irisin administration on HSPC stemness and pancytopenia‐related dysimmunity during BMF; however, the optimal protective effect of irisin on AA remains unknown.

  Irisin Pretreatment Reveals Enhanced Protective Response Upon Hematopoietic Reconstitution in the Acquired Aplastic Anemia Mouse Model · 2026 · DOI

• ABSTRACT Aim Standard laboratory housing (21°C) imposes chronic cold stress on mice, yet its fundamental impact on cardiac plasticity remains poorly defined.

  Thermoneutrality Reveals True Cardiac Adaptations to Exercise, Disease, and Aging in Male Mice · 2026 · DOI

• The liver gene expression of the peroxisomal β-oxidation enzyme acyl-coenzyme A oxidase 1 (ACOX1), which catabolizes very long chain fatty acids (VLCFA), increases in the context of obesity, but how this pathway impacts systemic energy metabolism remains unknown.

  Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling · 2024 · DOI

• The first limitation is regarding the metabolic memory that maintains GIPR-driven weight loss after GIPR has been switched off in adipose tissue. This phenomenon will require further definition with respect to potential epigenetic modifications associated with GIPR priming the adipocyte, in addition to target molecules that remain active in this memory state after returning to baseline conditions without ectopic receptor overexpression. A second limitation is that GIPR-induced weight loss mechanisms are distinct yet additive to the established GLP-1R agonist-based weight loss. Our follow-up studies will entail identifying the critical factor(s) that cause the GIPR-driven transient suppression in food intake. A third limitation is that our focus was to delineate the mechanism(s) by which GIPR has on the biology of the adipocyte and on energy balance. We acknowledge that these are preclinical studies, and as such, future clinical studies should address how applicable our proposed mechanism is in relation to incretin function in a clinical setting. Lastly, a broader range of Cell Metab. Author manuscript; available in PMC 2026 January 07. A u t h o r M a n u s c r i p t A u t h o r M a n u s c r i p t A u t h o r M a n u s c r i p t A u t h o r M a n u s c r i p t Yu et al. Page 16 conditions will be examined, including potential sexually dimorphic responses, as well as the fate of adipocytes following prolonged exposure to GIPR activation beyond the 12-week period reported here. This will further address the impact that chronic adipocyte-specific activation of GIPR has on healthspan and lifespan of mice.

  The GIP receptor activates futile calcium cycling in white adipose tissue to increase energy expenditure and drive weight loss in mice · 2024 · DOI

• 217 metabolic health. These findings pave the way for future research to explore the molecular targets identified here, potentially informing therapeutic strategies that can modulate macrophage-preadipocyte signalling to promote healthy adipose tissue expansion, and fat distribution, to help combat obesity-related metabolic disorders.

  Unveiling adipose populations linked to metabolic health in obesity · 2024 · DOI

• 215 6.4 Broader Implications for Adipose Tissue Function and Metabolic Health The insights gained from this thesis contribute to a deeper understanding of the biological underpinnings of regional adiposity, particularly the roles of oestradiol and macrophage-preadipocyte crosstalk. Depot-specific transcriptional responses to oestradiol and inflammation contribute to the understanding of sex-specific fat distribution patterns and their relevance to metabolic health. Women’s preferential accumulation of gluteal fat, and the maintenance of this adiposity, and its resistance to inflammatory perturbance, likely serves a protective role against metabolic dysregulation. Moreover, these results also highlight the importance of considering the macrophage-mediated effects of depot-specific adipose tissue biology, particularly in the context of oestradiol. The co-culture system revealed that macrophages are not passive bystanders but active regulators of preadipocyte fate and function. Macrophages drive anti-inflammatory states in co-culture systems, further contributing to signatures relating to lipolysis and fat storage, in response to oestradiol or stressors such as LPS. These interactions are critical for understanding how inflammation and hormonal signals converge to regulate fat storage and distribution, with significant implications for therapeutic approaches targeting metabolic disorders such as obesity, type 2 diabetes mellitus, and cardiovascular disease. 6.5 Future Directions The majority of this research employed cell culture systems and bioinformatics to investigate oestradiol responses in preadipocyte cell lines and explored how co-culture systems may modify these responses. Given that the MBDFAT cell lines utilised for the majority of this work exhibit lower ER-α expression compared to primary preadipocytes and differentiated preadipocytes, it would be valuable to replicate this study using primary preadipocytes and differentiated preadipocytes to determine whether they exhibit stronger transcriptional responses to oestradiol. Additionally, measuring intra-tissue concentrations of oestradiol and other relevant 216 6.6. Conclusion steroid hormones across different depots would help confirm that the in-vitro media measurements accurately reflect the depot-specific in-vivo production of oestradiol. Building upon the findings from the interactome analysis and bulk RNA sequencing of co-culture systems, future research should aim to validate the functional relevance of candidate preadipocyte-macrophage communication signals. This could be achieved by modulating the activation of these signals in-vitro and assessing the phenotypic outcomes (e.g proliferation, differentiation, lipid accumulation). Further investigations should then explore how this inter-cellular communication operates in-vivo to influence fat distribution, particularly in response to changes in oestradiol concentrations or varying metabolic states. Moreover, the observed link between steroid synthesis pathways and inflammatory stimuli warrants further exploration. Future studies should assess the concentrations of a comprehensive panel of steroid hormones, along with their receptors and relevant enzymes, in abdominal and gluteal adipocyte monocultures and co-cultures, with or without inflammatory stimuli. It would be valuable, also to repeat this analysis using tissue biopsies, across donors of different metabolic status (which should incorporate those with obesity-associated chronic inflammation), with a range of plasma oestradiol concentrations, and ideally also recruiting participants of differing cortisol status (e.g patients with Cushingoid disease). This approach would help clarify how depot-specific intra-tissue hormone production is modulated by macrophages, inflammation, and oestradiol, and how these factors contribute to variations in fat distribution phenotypes. 6.6 Conclusion In conclusion, this thesis provides a novel perspective on the role of macrophagepreadipocyte interactions in depot-specific responses to oestradiol and inflammation, revealing their molecular and cellular underpinning mechanisms.

  Unveiling adipose populations linked to metabolic health in obesity · 2024 · DOI

• 213 showed that lipopolysaccharide (LPS), an inflammatory stimulus, suppressed cellular proliferation pathways in abdominal preadipocytes. Indeed, co-culturing preadipocytes and macrophages was further observed to decrease inflammatory responses in preadipocytes, as compared to monocultured cells (explored in Section 5.3). Moreover, this signature may be permissive of tissue expansion, particularly in the gluteal region, where there was significant downregulation of genes associated with the suppression of adipocyte differentiation and tissue expansion (e.g STC2, SOD2, LIF), in adipocyte co-culture as compared to monoculture. Oestradiol treatment could further promote this anti-inflammatory signature, as the expression of key anti-inflammatory genes, such as CSF1/M-CSF, was increased in the gluteal depot with oestradiol treatment, alongside transcripts associated with fat metabolism and storage, including CES4. Meanwhile, opposite signatures, associated with decreased lipid accumulation, were upregulated in abdominal preadipocytes in response to oestradiol. Thus, oestradiol treatment in co-culture systems revealed a set of mechanisms by which oestradiol may modulate transcriptional signatures relating to sexual dimorphisms in fat storage. This suggested that the interplay between macrophages and preadipocytes creates depotspecific responses to oestradiol, demonstrating that adipose tissue health and function are not solely determined by adipocytes and preadipocytes but are also significantly shaped by macrophage-mediated signalling.

  Unveiling adipose populations linked to metabolic health in obesity · 2024 · DOI

• Research Questions Overall, this thesis firstly aimed to characterise adipose tissue stromal vascular fraction (SVF) populations, using single-cell RNA sequencing (scRNASeq) data to compare populations across different depots and sexes. This enabled a pioneering investigation into their transcriptional signatures. These novel insights highlighted the unique transcriptional biology of the female gluteal depot, which harboured a higher proportion of anti-inflammatory macrophage populations, and a greater abundance of immature preadipocyte populations (described in Section 3.3.2), which likely contribute to the cellular hyperplastic pool. Understanding the underlying biology of this depot is essential for elucidating the molecular mechanisms that promote the female pattern of fat distribution and its associated metabolic protection. This work subsequently aimed to investigate oestradiol responses in-vitro, using depot-specific preadipocyte cell line models. The complex and often contradictory findings within the current literature, regarding oestradiol’s effects on monocultured preadipocytes, were somewhat validated by the difficulty associated with measuring preadipocyte oestradiol responses. To elucidate these effects, it was necessary to compare the depot-specific transcriptomic landscape, in order to highlight the subtle 211 212 6.2.

  Unveiling adipose populations linked to metabolic health in obesity · 2024 · DOI

• 211 6.1 Research Questions........................... 211 6.2 Depot-Specific Responses to Oestradiol and Macrophage-Preadipocyte Interactions............................... 212 Inflammatory Responses and Their Impact on Adipose Tissue Function213 6.3 6.4 Broader Implications for Adipose Tissue Function and Metabolic Health.................................. 215 6.5 Future Directions............................ 215 6.6 Conclusion................................

  Unveiling adipose populations linked to metabolic health in obesity · 2024 · DOI

• A few studies have reported the potential relationship between mitochondrial pyruvate carrier 1 (MPC1) and inflammation, fibrosis, and insulin sensitivity in obese or NASH mouse models.

  Mitochondrial pyruvate carrier 1 regulates fatty acid synthase lactylation and mediates treatment of nonalcoholic fatty liver disease · 2023 · DOI

• The observed increase in protein expressions of both MPC1 and MPC2 during adipocyte differentiation of 3T3-L1 cells (Figure 1) has not been previously reported in 3T3-L1 cells, but MPC1 and MPC2 expression was shown to increase upon differentiation of leucine-rich repeat-containing G-protein coupled re- ceptor 5 (LGR5)+ intestinal stem cells (23).

  On Equality: I. Meritocracy and Equality. · 1972 · DOI

• Collectively, these findings indicate that chronic activation of mTORC1 in skeletal muscle promotes inflammatory remodeling but is insufficient to impair systemic glucose homeostasis, even under dietary stress.

  Constitutive mTORC1 Activation in Skeletal Muscle Increases Inflammation but is not Sufficient to Impair Glucose Tolerance · 2026 · DOI

• Ultimately, it remains to be determined whether these patterns will be seen in healthy humans and how they evolve in the setting of pathological metabolic and other disease states.

  Transcriptomic profiling of human brown and white adipose tissue depots · 2026 · DOI

• Overall, the existence and thus, the clinical relevance of age-related differences in DIT, remain unclear.

  Does Aging Affect Diet-Induced Thermogenesis? Revisiting the Evidence from Human Studies · 2026 · DOI

• In addition, we review the limited data available detailing how exercise may be used to combat obesity induced bone marrow dysfunction, and discuss future directions for research in this field.

  Hematopoiesis with Obesity and Exercise: Role of the Bone Marrow Niche · 2026 · DOI

• Exercise is a viable treatment option for deficits imposed by obesity and to combat immune dysfunction; however, the impact of exercise on the bone marrow niche is not well defined.

  Hematopoiesis with Obesity and Exercise: Role of the Bone Marrow Niche · 2026 · DOI

Most-cited papers in Adipose Tissue and Metabolism

• Temporal dynamics of the multi-omic response to endurance exercise training · Nature · 2024 · 230 citations
• Inhibition of IL-11 signalling extends mammalian healthspan and lifespan · Nature · 2024 · 205 citations
• The role of oxidative stress in the development of obesity and obesity-related metabolic disorders · Journal of Medical Biochemistry · 2020 · 192 citations
• Metrnl: a secreted protein with new emerging functions · Acta Pharmacologica Sinica · 2016 · 174 citations
• Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation · Nature Metabolism · 2024 · 132 citations
• Cardiometabolic characteristics of people with metabolically healthy and unhealthy obesity · Cell Metabolism · 2024 · 125 citations
• Exercise induces tissue-specific adaptations to enhance cardiometabolic health · Cell Metabolism · 2024 · 120 citations
• IgG is an aging factor that drives adipose tissue fibrosis and metabolic decline · Cell Metabolism · 2024 · 104 citations
• Sex-based differences in insulin resistance · Journal of Endocrinology · 2024 · 99 citations
• α-Ketoglutarate prevents hyperlipidemia-induced fatty liver mitochondrial dysfunction and oxidative stress by activating the AMPK-pgc-1α/Nrf2 pathway · Redox Biology · 2024 · 98 citations

Most recent work

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• BMPER induces the adipogenic differentiation of fibro/adipogenic progenitors and promotes intramuscular fat deposition in chickens · Journal of Animal Science and Biotechnology · 2026
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• Why Physiology Needs to Embrace Structural Biology ‐ The Hot Case of Thermogenic <scp>UCP1</scp> · Acta Physiologica · 2026
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• Angiotensin II and cAMP signaling pathways regulate mitochondrial biogenesis and activity in human adrenocortical cells. · bioRxiv · 2026

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