bims-mimead 2026-10-11 papers

Res Sq. 2026 Aug 12. pii: rs.3.rs-10603589. [Epub ahead of print]

An adipocyte-endothelial framework linking adipose tissue inflammation to cardiometabolic vulnerability in obesity.

Background Obesity-related cardiometabolic disease is linked to impaired adipose tissue function, but the underlying molecular programs are difficult to assign to specific adipose-resident cell types, to mechanistically connect to the activation state of macrophages, and to distinguish from alterations that may normalize with weight loss. Methods We integrated a layered design combining untargeted proteomics and lipidomics to define obesity-associated, cell-type-resolved molecular phenotypes across adipocytes and adipose microvascular endothelial cells, explore whether an inflammatory milieu reproduces adipose-resident cell dysfunction, and identify features that show evidence of recovery after weight loss. Next, we validated in adipose tissue transcriptomes the elements that exhibit the strongest association with dyslipidaemia, hypertriglyceridemia, and/or hyperglycaemia to identify gene signatures of cardiometabolic relevance. Results Adipocytes from subjects with obesity show suppression of mitochondrial energy metabolism together with impaired lipid plasticity, as reflected by triglyceride remodelling. By mimicking an inflammatory milieu with macrophage-conditioned media, we reproduced many of these changes in adipocyte cultures. Endothelial cells exhibited yet another, opposite trajectory in obesity, with reduced cell-cycle signalling and increased mitochondrial activation, which were recapitulated in vitro when these cells were exposed, respectively, to the secretions of inflamed macrophages and adipocytes. Bulk adipose tissue proteomes and lipidomes showed evidence of metabolic improvement after weight loss, including restoration of mitochondrial and substrate-handling pathways alongside reciprocal triglyceride remodelling. Together with inflammation-responsive adipocyte mitochondrial and lipid-handling dysfunction, our cell-type-informed framework probes macrophage and adipocyte-to-endothelial activation in obesity, and delineates cross-context cellular programs associated with weight loss. Notably, when integrated with transcriptomic resources, these layers of information prioritized determinants linked to impaired metabolism, and were used to generate models that can assess cardiometabolic vulnerability in subjects with obesity (AUROC values between 0.88 and 0.99). Conclusions Our study reveals adipocyte and endothelial cell-specific elements acting as molecular signatures of adipose tissue inflammation with cardiometabolic implications.

DOI: https://doi.org/10.21203/rs.3.rs-10603589/v1

Nat Metab. 2026 Oct 07.

Metabolic benefits of ketohexokinase inhibition in individuals with MASLD: a randomized placebo-controlled crossover trial.

High fructose consumption, particularly from sugar-sweetened beverages, contributes to cardiometabolic disease. Here we study the metabolic effects of 6-week pharmacological inhibition with PF-06835919 of ketohexokinase, the enzyme that catalyses the first committed step of fructose metabolism, in a randomized placebo-controlled crossover trial in 15 participants with metabolic dysfunction-associated steatotic liver disease. The primary outcome was hepatic insulin sensitivity, measured by insulin-stimulated suppression of endogenous glucose production. Secondary outcomes included fat distribution, peripheral and adipose tissue insulin sensitivity, and fat oxidation. While PF-06835919 treatment did not affect body weight, it improved hepatic insulin sensitivity and reduced intrahepatic lipid and saturated fatty acid content. Besides these beneficial hepatic effects, PF-06835919 also improved insulin-stimulated glucose disposal, adipose tissue insulin sensitivity, adipose tissue distribution and nocturnal fat oxidation. These changes are accompanied by changes in very low-density lipoprotein particle size distribution and circulating hepatokines. These results show that inhibition of fructose metabolism has beneficial metabolic effects that extend beyond the organs that metabolize fructose. ClinicalTrials.gov identifier: NCT05463575 .

DOI: https://doi.org/10.1038/s42255-026-01626-5

Obes Surg. 2026 Oct 07.

Impact of Bariatric Surgery on Reproductive Hormones and Menstrual Regularity in Women with Obesity.

Khaled Mosleh Torfa, George A Nashed, Stavro Paulo, Soha Hamed Ammar, Mohammed Elshwadfy Nageeb, Mohamed Yacoub.

BACKGROUND: Obesity affects 2.5 billion adults, disrupting the hypothalamic-pituitary-ovarian (HPO) axis through adipokine imbalance and aromatase activity. This causes hormonal dysregulation, infertility, and pregnancy risks. Bariatric surgery can restore hormonal balance and improve menstrual regularity. This study evaluates post-bariatric surgery changes in reproductive hormones and cycle regularity over six months in Egyptian women with obesity.
METHODS: This prospective cohort study included women aged 18-45 (BMI ≥ 35 kg/m²) undergoing laparoscopic bariatric surgery. Serum FSH, LH, estradiol, Progesterone, and AMH levels were measured at baseline, 3, and 6 months postoperatively. Secondary outcomes included menstrual regularity and hormonal correlations with weight loss.
RESULTS: Bariatric surgery resulted in a highly significant reduction in body weight and BMI over the six-month follow-up period (p < 0.001). Significant hormonal shifts were observed, including increased levels of FSH (p < 0.001) and LH (p = 0.001), a decreased LH/FSH ratio (p = 0.005), and marked reductions in estrogen and progesterone concentrations (p < 0.001). While AMH levels remained stable (p = 0.6), menstrual regularity improved significantly from 20% at baseline to 53.3% post-surgery (p = 0.001). Furthermore, the degree of weight loss was significantly and positively correlated with postoperative FSH and LH levels. The interventions were generally well-tolerated, with 82.4% of participants reporting no postoperative complications. No significant differences in the improvement of weight or hormonal profiles were noted between patients with and without PCOS.
CONCLUSION: Bariatric surgery induces weight loss and restores reproductive hormonal balance in women with obesity by improving HPO axis regulation. Increased FSH and LH levels, resulting from reduced adiposity, might contribute to improved menstrual regularity.
KEY POINTS: • Bariatric surgery resulted in a significant and progressive reduction in body weight and BMI over the six-month follow-up period (p < 0.001). • There was a significant postoperative increase in FSH and LH levels. Estrogen and progesterone concentrations demonstrated significant and sustained reductions post-surgery, whereas AMH levels remained stable throughout the study. • Menstrual regularity improved significantly, increasing from 20% of participants at baseline to 53.3% six months after surgery (p = 0.001). • The degree of weight loss was significantly and positively correlated with postoperative FSH and LH levels.

Keywords: AMH; Anti-müllerian hormone; Bariatric surgery; Estrogen; FSH; LH; Menstrual regularity; Obesity; Progesterone; Reproductive hormonal changes

DOI: https://doi.org/10.1007/s11695-026-08903-y

JCI Insight. 2026 Oct 06. pii: e206342. [Epub ahead of print]

Development of insulin resistance in women over the menopause transition.

Arun S Karlamangla, Wei Juan Han, Preethi Srikanthan, Albert Shieh, Duncan Thomas, Barbara Sternfeld, Monique M Hedderson, Gail A Greendale.

BACKGROUND: Body weight and insulin resistance in women increase in midlife. It is not known whether this is driven by the menopause transition or solely by chronological aging. We aimed to determine the role of the menopause transition and menopause-related BMI changes in the development of insulin resistance in midlife women.
METHODS: Mixed effects, linear spline modeling of longitudinal data in 1315 women, 42- to 52-years-old, pre- or early perimenopausal in 1995 to 1996 with up to 16 follow up visits by 2018. Homeostatic-model-assessed-insulin-resistance (HOMA-IR) was measured up to 12 times. Date of final menstrual period (FMP) was prospectively determined.
RESULTS: HOMA-IR increased faster over a 4-year interval extending from 1.5 years prior to 2.5 years after the FMP, than in the years before or after it; p value for both slope changes < 0.0001. In the referent woman (White, age 52 years at FMP, non-smoker, body mass index [BMI] 25.6 kg/m2 at baseline, and not on sex hormone therapy or statins), the average annualized rate of HOMA-IR increase, adjusted for covariates including changes in BMI, was 1.2%, 4.3%, and 0.9% respectively, before, during, and after the 4-year transition.
CONCLUSION: Consistent with an independent effect of the menopause transition, insulin resistance increased significantly faster during the transition (from 1.5 years before the to 2.5 years after the FMP) than in the years preceding or following the transition. Future studies need to investigate mechanisms underpinning this observed association and determine the impact of lifestyle on dampening menopause-associated increases in insulin resistance.
FUNDING: National Institutes of Health.

Keywords: Clinical Research; Diabetes; Endocrinology; Epidemiology; Population health research

DOI: https://doi.org/10.1172/jci.insight.206342

Nutr Res. 2026 Sep 19. pii: S0271-5317(26)00116-8. [Epub ahead of print]155 66-81

Açaí seed extract attenuates metabolic dysfunction and adipocyte hypertrophy by improving oxidative and inflammatory status in ovariectomized rats.

Mariana Alencar Cavalheira, Emilyn Molinaro da Silva, Matheus Pontes de Menezes, Dafne Lopes Beserra-Silva, Beatriz Cardoso de Oliveira, Iala Milene Bertasso, Patricia Cristina Lisboa, Caroline Fernandes-Santos, Cristiane Aguiar da Costa, Angela Castro Resende, Graziele Freitas de Bem, Dayane Teixeira Ognibene.

Menopause is a physiological transition characterized by the cessation of ovarian function and a decline in estrogen production, contributing to metabolic dysfunction, adipose tissue remodeling, oxidative stress, and chronic low-grade inflammation. Due to contraindications of hormone therapy for some women, natural compounds have been investigated. We hypothesized that açaí seed extract (ASE) would improve metabolic parameters and reduce white and brown adipose tissue (BAT) remodeling through antioxidant and anti-inflammatory mechanisms. Sprague-Dawley rats (90 days old) underwent bilateral ovariectomy (OVX), with Sham rats as controls. ASE supplementation (200 mg/kg/day) started 4 weeks after surgery and lasted 8 weeks. Food intake and body weight were assessed. Body composition was evaluated by nuclear magnetic resonance. After treatment, animals were euthanized by decapitation. Plasma lipid profile, 17 β-estradiol, leptin, and thyroid hormones were assessed. Retroperitoneal white adipose tissue (rWAT) and BAT were isolated for morphometric analysis and assessment of oxidative damage, antioxidant activity, and proinflammatory cytokines. UCP-1 immunostaining was evaluated in BAT. 17 β-estradiol concentrations and uterine weight were reduced by OVX and were not modified by ASE. ASE attenuated OVX-induced alterations in body fat mass, dyslipidemia, leptin, and total T3; prevented adipocyte hypertrophy in rWAT; reduced interleukin 6 and oxidative damage; and improved antioxidant activity in rWAT and BAT. The extract reduced body weight gain, body fluid, and tumor necrosis factor alpha concentrations and increased UCP-1 immunostaining, independent of ovarian status. The results suggest that ASE has potential to mitigate metabolic alterations associated with OVX, with some effects occurring independently of ovarian status.

Keywords: Adipose tissue; Antioxidant; Euterpe oleracea Mart.; Menopause; Polyphenols

DOI: https://doi.org/10.1016/j.nutres.2026.09.006