bims-mimead 2026-08-09 papers

Diabetes Res Clin Pract. 2026 Aug 02. pii: S0168-8227(26)00400-6. [Epub ahead of print]239 113480

Adipose tissue insulin resistance, not muscle insulin resistance, is associated with impaired metabolic health in humans.

Kiana Meshkat, Anouk Gijbels, Lydia A Afman, Gijs H Goossens, Ellen E Blaak, Ruth C R Meex.

AIM: Obesity is a major contributor to insulin resistance (IR) and cardiometabolic diseases, but IR can manifest in a tissue-specific manner, resulting in discordant IR phenotypes. This study characterized metabolic and clinical differences between individuals with adipose and muscle IR.
METHOD: Baseline data from 229 adults (40-75 years, BMI 25-40 kg/m2) in the PERSON study were analyzed. Participants were categorized into four groups based on indices of muscle and adipose insulin sensitivity. Muscle IR was assessed with a 7-point oral glucose tolerance test, and adipose IR was determined from fasting plasma insulin and non-esterified fatty acids. Detailed phenotyping was performed under controlled conditions and daily life.
RESULTS: 42% of participants displayed discordant IR patterns. Independent of muscle IR, adipose IR was associated with an adverse cardiometabolic profile, including abdominal fat accumulation, higher fasting insulin, HOMA-IR and triglycerides, greater glycemic variability, and more liver fat and hepatic IR. In contrast, individuals with isolated muscle IR maintained a relatively healthy cardiometabolic profile, though women exhibited higher muscle fat infiltration and hepatic IR.
CONCLUSION: These findings demonstrate that adipose IR is more strongly and consistently linked to impaired metabolic health than muscle IR, highlighting the importance of phenotype-specific strategies for prevention and treatment.

Keywords: Adipose tissue; Cardio-metabolic health; Insulin resistance; Obesity; Skeletal muscle; Type 2 diabetes

DOI: https://doi.org/10.1016/j.diabres.2026.113480

J Nutr. 2026 Aug 07. pii: S0022-3166(26)00422-0. [Epub ahead of print] 101773

Metabolic, endocrine and appetite responses to carbohydrate versus niacin ingestion during exercise in healthy females and males.

Louise Bradshaw, Alfonso Moreno-Cabañas, Bruno Spellanzon, Katie Hutchins, Ben Narang, Adam J Collins, Francoise Koumanov, James A Betts, Javier T Gonzalez.

BACKGROUND: The substrates used during exercise may influence the post-exercise response of systemic metabolites and hormones, along with the drive to refeed following exercise. However, no study has assessed whether manipulating substrate metabolism during exercise independent from carbohydrate ingestion alter these responses.
OBJECTIVE: To assess the effects of niacin and carbohydrate ingestion during exercise on post-exercise metabolite and hormone concentrations, and ad libitum energy intake.
METHODS: Fifteen participants (five female) performed one hour of cycling at 95% lactate threshold1 with carbohydrate ingestion (CARB, insulin-induced lipolysis suppression), niacin ingestion (NIACIN; insulin-independent lipolysis suppression) and fasted (FAST), in a crossover design with blood and breath samples. Two hours after exercise, energy intake was measured at an ad libitum meal. The study was registered on clinicaltrials.gov/study/NCT05417659.
RESULTS: Compared with FAST, CARB and NIACIN suppressed plasma NEFA concentrations during exercise (time x condition: p<0.001) and total fat oxidation (mean±95%CI; CARB: -11±4 g, p<0.001; NIACIN: -9±5 g, p=0.001). CARB and NIACIN increased plasma GLP-1TOTAL concentrations compared to FAST (time x condition interaction: p<0.001), with the highest concentrations in CARB (p<0.001 vs FAST and NIACIN). There was no evidence of differences in ad libitum energy intake between conditions (FAST 833 ± 206 kcal, CARB 786 ± 219 kcal, NIACIN 780 ± 158 kcal: p=0.37). Ketone body and (large) very-low-density lipoprotein-triglyceride (VLDL-TG) concentrations were lower with NIACIN vs FAST (time x condition: both p<0.001), whereas branched-chain amino acid (BCAA) concentrations were lower with CARB vs FAST (time x condition: p<0.001).
CONCLUSIONS: These data demonstrate that niacin ingestion increases carbohydrate oxidation during exercise and post-exercise GLP-1, ketone body and VLDL-TG concentrations but does not seem to detectably influence post-exercise energy intake. This suggests that manipulating fatty acid availability during exercise may have greater implications for metabolism than for energy balance behaviours.

Keywords: Energy balance; appetite hormones; carbohydrate insulin model; lipolysis; metabolism; substrate utilisation

DOI: https://doi.org/10.1016/j.tjnut.2026.101773

Geroscience. 2026 Aug 07.

Aging is associated with altered estrogen receptor expression and alters redox protein balance in human female skeletal muscle.

Andrea Tamariz-Ellemann, Line Boel Nørregaard, Mikkel Oxfeldt, Line Barner Dalgaard, Susana Novella, Mette Hansen, Ylva Hellsten, Lasse Gliemann.

It has been hypothesized that age‑related declines in skeletal muscle and vascular function in females may be partly estrogen‑dependent. This study investigated skeletal muscle protein expression of estrogen receptor α (ERα), estrogen receptor β (ERβ), and G protein-coupled estrogen receptor 1 (GPER1), and their association with proteins involved in redox regulation and vascular function, in relation to age, menopausal status, and lifelong physical activity. Skeletal muscle biopsies were obtained from 107 healthy females aged 19-70 years, including 26 postmenopausal females who were lifelong exercise trained. Protein expression of ERα, ERβ, GPER1, and downstream redox‑ and vascular‑related proteins was quantified. Age‑ and menopause‑related differences, associations between protein targets, and effects of lifelong exercise were examined. ERα protein expression was lower in older females with a 48% lower expression in the ≥ 55 years age group compared with the < 30-year group. GPER1 protein expression was 22% lower across all older age groups compared with the < 30-year group. ERβ expression was reduced in mid‑life (45-59 years) but not in the oldest age group. Both ERα and ERβ were positively correlated with endothelial nitric oxide synthase (eNOS) expression, whereas GPER1 showed no association with eNOS. ERβ expression was associated with pro‑oxidative NOX2 expression. Aging in females is associated with a lower ERα and GPER1 protein expression in skeletal muscle. Furthermore, lower ER expression by aging is associated with a lower eNOS expression, indicating associations with proteins involved in nitric oxide-related redox regulation in skeletal muscle in aged females.

Keywords: Estrogen receptors; Females vascular aging; Menopause; Oxidative stress; Skeletal muscle

DOI: https://doi.org/10.1007/s11357-026-02432-3

J Endocrinol. 2026 Aug 03. pii: JOE-26-0176. [Epub ahead of print]

Rapamycin-induced fatty liver in mice is attenuated by chloroquine co-treatment in an ERRα-dependent manner.

Wafa B'chir, Catherine R Dufour, Sylvia Andrzejewski, Julie St-Pierre, Charlotte Scholtes, Vincent Giguère.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), remains a major health concern world-wide. Hepatic steatosis manifests by the aberrant accumulation of lipids in hepatocytes. We have previously shown that pharmacological inhibition of mTOR complex 1 (mTORC1) by rapamycin, a widely utilized potent immunosuppressant, induces MASLD under normal conditions. Notably, this phenotype was found exacerbated in mice with genetic or pharmacological inhibition of the master transcriptional regulator of energy metabolism, nuclear receptor ERRα. In this study, we show that combining antimalaria drug chloroquine with rapamycin attenuates the severity of hepatic lipid deposition observed with rapamycin monotherapy. Bulk mRNA-seq profiling showed that chloroquine co-injection reverses the upregulation of a large proportion of genes linked to lipid metabolism homeostasis found induced by rapamycin alone. Interrogation of these genes for direct transcriptional regulators identified ERRα among top candidates. Using a mouse model with genetic ERRα ablation, we demonstrate a crucial dependency on ERRα activity for the observed amelioration of rapamycin-induced hepatic steatosis by chloroquine addition. In ERRα-null liver, chloroquine failed to reverse, and in some instances aggravated the upregulation of lipid metabolism genes by rapamycin, with evidence linking the impaired management of hepatic lipid overload to underling mitochondrial dysfunction. Together, these findings underscore a critical role of ERRα in reversing MASLD.

Keywords: RNA-seq; chloroquine; fibrosis; hepatic steatosis; lipid metabolism; mitochondria; nuclear receptor; transcription

DOI: https://doi.org/10.1530/JOE-26-0176