bims-mimead 2026-06-07 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2026–06–07
six papers selected by
Rachel M. Handy, University of Guelph and Universiteit Mastricht

Decreased degree of adipocyte differentiation in visceral adipose tissue contributes to metabolic dysfunction-associated steatotic liver disease.
Long-term effect of sweeteners and sweetness enhancers on gene expression markers of adipose tissue function, adipocyte morphology, and metabolic health: a SWEET substudy.
Excess glucose shapes mitochondrial metabolism and redox state in human primary white adipocytes.
Targeting hypothalamic SIK3 to promote weight loss and improve glycemic control in mice.
DICER-driven regulation of lipid metabolism and macrophage-adipocyte crosstalk in partial lipodystrophy.
Adipose cellularity and long-term development of impaired glucose metabolism: Swedish cohort study from 1988 through 2016.

Nat Commun. 2026 Jun 03.

Decreased degree of adipocyte differentiation in visceral adipose tissue contributes to metabolic dysfunction-associated steatotic liver disease.

Kyla Z Gelev, Seung Hyuk T Lee, Marcus Alvarez, Rosellina M Mancina, Federica Tavaglione, Oveis Jamialahmadi, Umberto Vespasiani-Gentilucci, Asha Kar, Zitian Wang, Dorota Kaminska, Minna U Kaikkonen, Ville Männistö, Sini Heinonen, Tuure Saarinen, Anne Juuti, Kirsi H Pietiläinen, Jussi Pihlajamäki, Stefano Romeo, Päivi Pajukanta.

The mechanisms connecting the human fat depots, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), to metabolic dysfunction-associated steatotic liver disease (MASLD) remain elusive. We hypothesize that in individuals with obesity, a decreased degree of adipocyte differentiation may contribute to ectopic fat accumulation in the liver, seen in MASLD. Here we show, using single nucleus RNA-sequencing from adipose tissue biopsies, that the predicted degree of VAT adipocyte differentiation is decreased in individuals with MASLD, with an attenuated impact observed in SAT adipocytes. Next, we discover that regional variants of the VAT adipocyte differentiation gene set explain a substantial proportion (17%) of MASLD heritability. These genes largely overlap (>50%) with adipocyte genes differentially expressed by MASLD, regulated by variants in cis. Finally, we show that these genes are linked to smaller adipocyte size. Together, our findings reveal that a decreased predicted degree of VAT adipocyte differentiation contributes to MASLD.

DOI: https://doi.org/10.1038/s41467-026-73660-6
Int J Obes (Lond). 2026 Jun 02.

Long-term effect of sweeteners and sweetness enhancers on gene expression markers of adipose tissue function, adipocyte morphology, and metabolic health: a SWEET substudy.

SWEET consortium

BACKGROUND/OBJECTIVES: We investigated the effects of sweeteners and sweetness enhancers (S&SEs) in replacement of sugar on gene expression markers of adipose tissue (AT) function, adipocyte morphology, and metabolic health in adults during weight maintenance (WM) following weight loss (WL).
SUBJECTS/METHODS: As part of a randomized controlled trial (European SWEET-project), 83 adults were enrolled in the study, which consists of a dietary intervention, comprising a 2-month WL-phase and a 10-month WM-phase during which participants followed a healthy diet (<10E%-added sugar) with (S&SEs group) or without S&SEs (sugar group). At baseline, after WL, and at the end of WM, we determined body composition, whole-body/tissue-specific insulin sensitivity (oral glucose tolerance test), abdominal subcutaneous adipocyte size and AT gene expression.
RESULTS: WL decreased adipocyte size and improved insulin sensitivity (both P < 0.001), which was accompanied by a significant downregulation of genes involved in adipogenesis (CEBPɑ, P = 0.004), fatty acid uptake (LPL and SREBF1, both P < 0.001), fatty acid synthesis (FASN and SCD, both P < 0.001), intracellular lipolysis (ATGL, P < 0.001; HSL, P = 0.001), leptin (LEP, P < 0.001), and mitochondrial function (CS, P = 0.048) in AT. The S&SEs-group tended to regain less weight than the sugar group during the WM-phase (3.0 ± 1.2 vs. 5.9 ± 1.0 kg, respectively; P = 0.050). During the WM-phase, the S&SEs group showed a less pronounced increase in AT LPL gene expression (P = 0.041), while ABHD5 expression decreased compared to the sugar group (P = 0.036). No group differences in adipocyte size, expression of genes involved adipogenesis/oxidative metabolism/inflammation, the sweet taste receptor TAS1R3 and insulin sensitivity were found.
CONCLUSIONS: S&SE-intake during a 10-month WM-phase following WL altered AT gene expression of lipolytic markers, without affecting adipocyte morphology and insulin sensitivity in adults with overweight/obesity.
TRIAL REGISTRATION: ClinicalTrials.gov NCT04226911, Sweeteners and Sweetness Enhancers: Prolonged Effects on Health, Obesity and Safety (SWEET).

DOI: https://doi.org/10.1038/s41366-026-02117-z
Free Radic Biol Med. 2026 Jun 03. pii: S0891-5849(26)00825-7. [Epub ahead of print]

Excess glucose shapes mitochondrial metabolism and redox state in human primary white adipocytes.

Elena Herbers, Kari Moisio, Ruben Torregrosa-Muñumer, Jari E Karppinen, Sini Heinonen, Birgitta W van der Kolk, Antti Hassinen, Hilkka Peltoniemi, Reetta Tuominen, Eija Pirinen, Ville Hietakangas, Liliya Euro, Kirsi H Pietiläinen.

  Mitochondrial dysfunction in white adipose tissue (WAT) is a hallmark of obesity, yet nutrient-driven responses in adipocytes remain poorly defined, partly due to widespread use of supra-physiological glucose-rich media in in vitro adipocyte models. We used integrated transcriptomics, fluxomics, and functional analyses to assess how glucose availability shapes mitochondrial metabolism and redox status during human adipocyte differentiation. Primary human adipocytes (n = 6 donors) were differentiated in commonly used media containing high glucose (DMEM/F12, 17.6 mM; DMEM/HG, 25 mM), physiological glucose (LG, 5.5 mM), or galactose (Gal, 25 mM). High-glucose conditions were associated with a shift from oxidative phosphorylation toward glycolysis, reduced mitochondrial biogenesis, NADH accumulation, and elevated mitochondrial reactive oxygen species, accompanied by impaired insulin sensitivity, reduced adiponectin secretion, together with transcriptional signatures of inflammatory and stress-associated responses. Fluxomics revealed altered pyruvate flux, enhanced anaplerotic pathways, and upregulated anabolic programs. In contrast, LG and Gal conditions preserved mitochondrial and redox features, more closely resembling characteristics of healthy WAT. Collectively, these data define a metabolic phenotype, in which supra-physiological glucose is associated with redox imbalance and metabolic reprogramming in human adipocytes under defined in vitro conditions. Our results highlight the importance of physiological glucose for adipocyte metabolism modeling and provide a framework for interpreting nutrient effects on mitochondrial and redox phenotypes.

Keywords:  adipocyte; glycolysis; high glucose; metabolic reprogramming; mitochondrial dysfunction; redox stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.321
Nat Commun. 2026 Jun 02.

Targeting hypothalamic SIK3 to promote weight loss and improve glycemic control in mice.

Danise Ann Onda, Chieh-Hsin Yang, Callen Goldsmith, Cait A Beddows, Rui Qi Teo, Lei Zhang, XiaoZhuo Yuan, Yifei Zhu, Man Ks Lee, Ashley J Ovens, Dingyi Yu, Kei Sakamoto, John W Scott, Andrew J Murphy, Noriyuki Tsumaki, Herbert Herzog, Garron T Dodd, Kim Loh.

Salt-Inducible Kinase 3 (SIK3) has emerged as a key regulator of peripheral metabolism, however its cellular and molecular function in regulating body weight and energy metabolism, particularly in hypothalamic neurons, remains unclear and largely unexplored. Here, we demonstrate that SIK3 expression is elevated in the hypothalamus of obese mice. Inactivation of SIK3 specifically in orexigenic NPY neurons reduces food intake, increases energy expenditure, and enhances white adipose tissue browning, resulting in resistance to high-fat diet-induced obesity in mice. Pharmacological inhibition of SIK3 with the inhibitor GLPG3970 in diet-induced obese mice led to significant reductions in body weight and adiposity, primarily due to decreased energy intake, with notable improvements in metabolic health. These effects are linked to enhanced central leptin and insulin signaling, and the dephosphorylation and nuclear translocation of key transcriptional metabolic regulators, CRTC1 and HDAC5. These findings reveal a previously unidentified SIK3-mediated pathway that promotes positive energy balance and suggests SIK3 inhibition may offer therapeutic potential for treating obesity and metabolic disorders.

DOI: https://doi.org/10.1038/s41467-026-73649-1
Biomed Pharmacother. 2026 Jun 03. pii: S0753-3322(26)00584-6. [Epub ahead of print]200 119548

DICER-driven regulation of lipid metabolism and macrophage-adipocyte crosstalk in partial lipodystrophy.

Andréa L Rocha, Rhaissa Godoi, Tanes Imamura de Lima, Diogo de Moraes, Bruna Brasil Brandão, Antonio F M Pinto, Heloísa Antoniella Braz-de-Melo, Felipe Corrêa da Silva, Tiago Tomazini Gonçalves, Letícia de Souza Figueiredo, João Pedro Mazzi, Niedson Correia de Lima Junior, Safira Maria Leite Sousa, Josiane Erica Miyamoto, Luiz Osório Leiria, Jan-Wilhelm Kornfeld, Kelly Grace Magalhães, Pedro Manoel Moraes-Vieira, Alan Saghatelian, Marcelo A Mori.

  Partial lipodystrophy is characterized by abnormal fat distribution, impaired thermogenesis, systemic inflammation, and diminished DICER1 expression in adipose tissue. Using adipocyte-specific Dicer1-deficient murine models to mimic lipodystrophy, we identified early metabolic and inflammatory alterations associated with the onset of partial lipodystrophy. DICER deficiency in adipocytes impaired lipid metabolism, leading to increased release of saturated lipids and triglycerides into the medium while reducing the biosynthesis of anti-inflammatory lipids. These changes promoted a pro-inflammatory environment by inducing macrophages to release IL-1β. In parallel, both adipocyte-autonomous DICER deficiency and the resulting inflammatory environment impaired adipocyte thermogenic capacity. Lipidomic analyses revealed reduced levels of docosahexaenoic acid (DHA) and other polyunsaturated fatty acids (PUFAs) in Dicer1-deficient adipocytes, accompanied by increased expression of genes encoding CYP450 enzymes linked to lipid degradation, and reduced DHA biosynthesis. Co-culture experiments confirmed that Dicer1-deficient adipocytes exacerbate macrophage-driven pro-inflammatory profile and thermogenic gene suppression. Notably, DHA supplementation mitigated the pro-inflammatory response triggered by conditioned media from Dicer1-deficient adipocytes. These findings reveal a critical role for adipocyte DICER in regulating lipid metabolism, macrophage-adipocyte interactions, and thermogenic function, offering new insights into molecular mechanisms driving metabolic dysfunction and chronic inflammation associated with partial lipodystrophy.

Keywords:  Adipocyte; DICER; Lipidomics; Lipodystrophy; Macrophage; Thermogenesis

DOI:  https://doi.org/10.1016/j.biopha.2026.119548
EBioMedicine. 2026 Jun 02. pii: S2352-3964(26)00181-7. [Epub ahead of print]128 106299

Adipose cellularity and long-term development of impaired glucose metabolism: Swedish cohort study from 1988 through 2016.

Peter Arner, Thorkild I A Sørensen, Daniel P Andersson.

   BACKGROUND: Adipocyte volume and number form adipose tissue cellularity, and adipocyte volume relates to impaired glucose metabolism (IGM). We studied how the cellularity relates to future long-term IGM development.
METHODS: We investigated 1014 participants living in Stockholm, Sweden 1986-2016 for abdominal subcutaneous adipocyte volume and number and IGM (impaired fasting glucose (≥6.1 mmol/l) and/or type 2 diabetes). A re-examination was conducted 2018-2022 on 241 participants (after on average 15 years); 127 remained without IGM, 47 had developed IGM and 43 remained as IGM. We compared baseline adipocyte volume and number for the three groups by analysis of variance and studied the odds ratio for future IGM as compared with always being healthy by logistic regression, correcting for relevant co-factors.
FINDINGS: Subcutaneous adipocytes were 20% larger in those having IGM from start or developed it later compared with those without IGM throughout (p = 0.005-0.03). Subcutaneous adipocyte number was similar in all three groups (p = 0.26). By comparing upper and lower tertiles for adipocyte volume/number the odds ratio for developing IGM was 2.8 (95% confidence interval CI; 1.2-6.5) for large adipocytes and 0.8 (0.4-2.0) for many adipocytes. Large adipocytes as a risk factor for future IGM was independent of sex, age, observation time, waist-to-hip ratio, body fat, physical activity or undergoing bariatric surgery, but not of insulin resistance measure, which strongly associated with adipocyte volume (r = 0.65).
INTERPRETATION: Adipocyte volume, but not number, associates with risk of long-term development of IGM. Large adipocytes confer this increased risk, maybe through insulin resistance.
FUNDING: The Stockholm County Council (963296, 994175, 986118), the Centre for Innovative Medicine at Karolinska Institutet (986109), and the Swedish Society of Medicine (1001156). The Novo Nordisk Foundation supports the Novo Nordisk Foundation Center for Basic Metabolic Research (grants NNF18CC0034900 and NNF23SA0084103). None of the funding sources had any involvement in the study.

Keywords:  Adipocyte number; Adipocyte volume; Impaired fasting glucose; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.ebiom.2026.106299