bims-mimead 2026-05-17 papers

Issue of 2026–05–17
five papers selected by
Rachel M. Handy, University of Guelph

bioRxiv. 2026 Feb 23. pii: 2026.02.22.706993. [Epub ahead of print]

Hepatocyte Estrogen Receptor α Mediates Estrogen-induced Augmentation of Hepatic Mitochondrial Respiration Following Ovariectomy.

Edziu Franczak, Benjamin A Kugler, Sebastian F Salathe, Julie A Allen, Colin S McCoin, E Matthew Morris, John P Thyfault.

Whole-body estrogen receptor α (ERα) knockout mice develop hepatic steatosis; however, liver-specific ERα knockout (LERKO) mice fail to recapitulate this susceptibility and maintain normal hepatic mitochondrial function. However, estrogen-mediated protection against hepatic steatosis is lost in LERKO mice following ovariectomy (OVX). Here, we tested whether loss of hepatic ERα blunts estrogen modulation of hepatic mitochondrial respiratory capacity and mitochondrial proteome following ovariectomy (OVX). Sham or ovariectomy (OVX) surgery was performed in middle-aged female mice (36-40 weeks), followed by AAV injection to generate Control (Con; GFP) or LERKO mice (Cre). All mice were placed on a high-fat diet (HFD) for 10 weeks following surgery. Half of the OVX mice received 17-beta estradiol (E2) replacement (OVX+E2) for the last 4 weeks of HFD. OVX mice had greater body mass and adiposity, which was reversed by E2 replacement in both Con and LERKO mice. While E2 replacement reduced steatosis in both Con and LERKO OVX mice, the LERKO OVX mice maintained greater hepatic triglyceride content. E2 replacement promoted greater basal and ADP-stimulated (State 3) mitochondrial respiration in Con OVX but not in LERKO OVX mice under palmitate-supported conditions. Changes in mitochondrial respiration could not be attributed to altered responses to changes in energy demand (G ATP ) or to alterations in mitochondrial H 2 O 2 production. Conversely, maximal coupled branched-chain amino acid-supported respiration was universally suppressed by E2 replacement. Proteomics analysis revealed E2-mediated reductions in hepatic mitochondrial energy transduction, with relatively minimal differences between Con and LERKO mice. In conclusion, post-ovariectomy estrogen treatment reduces steatosis in the absence of hepatic ERα; however, triglyceride levels remain higher, and mitochondrial respiratory deficits persist despite similar proteomic signatures, suggesting that ERα signaling is required for optimal estrogen hepatic responsiveness.

DOI: https://doi.org/10.64898/2026.02.22.706993

Diabetologia. 2026 May 12.

Nocturnal fat oxidation is lower in older individuals with overweight/obesity, including those with type 2 diabetes, and is associated with fasting triglyceride levels.

Soraya S de Kam, Jeroen H P M van der Velde, Anna Veelen, Johanna A Jörgensen, Joris Hoeks, Patrick Schrauwen.

AIMS/HYPOTHESIS: We previously showed that nocturnal fat oxidation is reduced in older individuals with overweight/obesity and impaired glucose tolerance and insulin sensitivity compared with young lean individuals. Here, we compared nocturnal energy expenditure and substrate oxidation across groups varying in age, body composition and metabolic status to unravel factors underlying variations in nocturnal substrate metabolism.
METHODS: Data were collected from 18 previously conducted human clinical studies (N=187), all performed under conditions of energy balance with similar diet composition and meal timing. Individuals were categorised into four groups: young lean (YL); older lean (OL); older with overweight/obesity (OBE); and older with overweight/obesity and type 2 diabetes (T2D). Nocturnal energy expenditure and substrate oxidation were determined by whole-room indirect calorimetry, body composition was assessed by air-displacement plethysmography or dual energy x-ray absorptiometry, and glucose, insulin, HOMA-IR, NEFA and triglycerides were measured from fasted blood samples. Group comparisons for nocturnal energy expenditure and substrate oxidation were performed using Kruskal-Wallis tests, and over time using linear mixed models including group × time interactions, with Bonferroni correction applied to both analyses. Multivariate linear regression analysis was applied to identify whether age, sex, HOMA-IR, fasting NEFA, fasting triglycerides, fat mass and fat-free mass were independent factors of nocturnal energy expenditure and substrate oxidation.
RESULTS: Nocturnal energy expenditure, adjusted for fat-free mass, was higher in OBE compared with YL and OL (p<0.01 for both); it was also higher in T2D compared with OL (p<0.01). Nocturnal fat oxidation, expressed as a percentage of energy expenditure, was lower in OBE (median: 46.28%, IQR: 37.74-53.05) and T2D (median: 46.48%, IQR: 41.05-53.65) compared with YL (median: 52.95%, IQR: 47.82-57.61; p<0.01 for both) and OL (median: 55.21%, IQR: 54.15-58.89; p<0.01 for both). Standardised linear regression models revealed that fasting triglycerides were positively associated with nocturnal respiratory exchange ratio (β=0.337; 95% CI 0.165, 0.508) and nocturnal carbohydrate oxidation (% of energy expenditure; β=0.337; 95% CI 0.166, 0.509), and inversely associated with nocturnal fat oxidation (% of energy expenditure; β=-0.352; 95% CI -0.520, -0.813).
CONCLUSIONS/INTERPRETATION: Nocturnal fat oxidation (% of energy expenditure) is diminished in older individuals with overweight/obesity, irrespective of diabetes status. No differences in nocturnal energy expenditure (adjusted for fat-free mass) or substrate oxidation were observed between young and older lean individuals, suggesting that age per se may not strongly influence nocturnal substrate metabolism. Fasting triglyceride level was the strongest associated factor of nocturnal substrate oxidation.

Keywords: Energy expenditure; Indirect calorimetry; Metabolic flexibility; Nocturnal fat oxidation; Obesity; Substrate metabolism; Type 2 diabetes

DOI: https://doi.org/10.1007/s00125-026-06736-z

Am J Physiol Endocrinol Metab. 2026 May 14.

Acute overfeeding impairs meal-stimulated adipose tissue microvascular blood flow in healthy adults independent of changes in adiposity.

Barbara Brayner, Shaun Mason, Elmira Karimi, Michelle A Keske, Katherine M Roberts-Thomson, Lewan Parker, Andrew C Betik, Hannah J Thomas, Kimberley L Way, Katherine M Livingstone, D Lee Hamilton, Gunveen Kaur.

Subcutaneous adipose tissue microvascular blood flow (MBF) increases in response to insulin or a meal, with gastric inhibitory polypeptide (GIP) being a proposed mechanism. This vascular response is blunted in people with insulin resistance, obesity and type 2 diabetes. The blunted MBF response is implicated in reduced nutrient delivery and increased chronic disease risk. Recently we have shown that acute overfeeding causes hyperinsulinemia and impairs meal-induced skeletal muscle MBF in healthy people without inducing adiposity. But it is not known if acute overfeeding impacts adipose tissue MBF and plasma GIP concentrations. We studied the impact of a 7-day high-calorie high-fat (HCHF) diet intervention on body composition, post-prandial plasma GIP concentrations and truncal subcutaneous adipose tissue MBF responses to a mixed meal challenge (MMC) in healthy adults (n=14). Experimental procedures were performed on day 0 (pre), 4 (mid) and 8 (post-intervention). Seven days of HCHF diet intervention did not change total, trunk, gynoid, android or visceral fat. Adipose tissue MBF increased above baseline at 60 min following the MMC at pre- (p=0.002) and mid-intervention (p=0.007), and but not at post-intervention (p = 0.231). Plasma GIP concentrations significantly increased at all timepoints (all p<0.001) from 0 to 120 min following the MMC with no differences between pre- and post-intervention. In conclusion, acute overfeeding in healthy individuals leads to a blunting of meal-induced adipose tissue MBF without changes in adiposity or changes in plasma GIP. Future studies should investigate other potential mechanisms behind the HCHF diet-induced vascular impairments to prevent chronic disease risk.

Keywords: Microvascular blood flow; adipose tissue; gastric inhibitory polypeptide; high-calorie high-fat diet; insulin resistance; overfeeding

DOI: https://doi.org/10.1152/ajpendo.00028.2026

J Physiol. 2026 May 11.

Δ9 Tetrahydrocannabinol and cannabis extracts differentially improve adipoinsular dysfunction in diet-induced obesity.

Bryant Avalos, Martin Olmos, Courtney P Wood, Camila Alvarez, Haley M Read, Parima Udompholkul, Theodore Garland, Nicholas V DiPatrizio.

Diet-induced obesity (DIO) is associated with dysregulated adipoinsular axis and endocannabinoid system (eCBS) function. Acute cannabis consumption stimulates appetite; however, chronic consumption is paradoxically associated with lower prevalence of human obesity and type 2 diabetes. We investigated the impact of chronic exposure to Δ9 tetrahydrocannabinol (THC) and cannabis extracts on DIO and glucose homeostasis in mice. Male mice were fed a high-fat/sucrose diet or a low-fat/no-sucrose diet for 60 days. At day 30, mice were administered THC (5 mg/kg) or cannabis extracts matched for THC content daily for 30 days. We assessed adipocyte biology, glucose tolerance, insulin sensitivity, eCBS expression, body weight, food intake and motor activity. Roles for the eCBS in cannabis-induced changes in metabolic processes, including cellular bioenergetics, were analysed in 3T3-L1 adipocytes. THC and extracts reduced body weight and fat mass in DIO mice, and reversed DIO-associated changes in expression of adipokines that regulate the adipoinsular axis. Extracts normalized expression of adipokines more effectively than THC. Notably, extracts - but not THC - normalized glucose clearance in DIO mice to levels found in lean mice. In addition, THC and extracts promoted anti-adipogenic effects and changes in energy metabolism in 3T3-L1 cells in a concentration-dependent manner. These studies suggest that chronic cannabinoid exposure improves metabolic function and dysregulated glucose homeostasis in DIO by a mechanism that includes restoring impaired adipoinsular axis function. KEY POINTS: Δ9 Tetrahydrocannabinol (Δ9THC) and cannabis extracts reduce body weight and fat mass in obese mice. Cannabis extracts, but not Δ9THC alone, improve glucose homeostasis in obese mice. Extracts more effectively normalize expression of components of the adipoinsular axis in obese mice. Δ9THC and extracts promote anti-adipogenic effects in 3T3-L1 cells. Δ9THC and extracts alter cellular bioenergetics in 3T3-L1 cells.

Keywords: 3T3‐L1; CB1; THC; adipose; cannabis; endocannabinoid; obesity

DOI: https://doi.org/10.1113/JP290431

Adipocyte. 2026 Dec 31. 15(1): 2671558

A non-invasive method for light-inducible knockout across all cell types in mouse subcutaneous adipose tissue.

Erica de Sousa, Magdalena Blaszkiewicz, Kristy Townsend.

Cre recombination is a widely used technique for mechanistic insights in physiology and disease. However, available constitutive and inducible Cre systems present challenges that can be prohibitive for some study designs. For example, Cre expression can result in cell types targeted across numerous tissues and organs, or when a gene is expressed across multiple cell types in a tissue, Cre-Lox restricted knockout will not enable ablation across an entire tissue or organ. Photoactivatable Cre (PA-Cre) systems enable temporally and spatially restricted gene expression control in delimited anatomical regions, typically requiring a micro-LED or fibre optic implantation. Here, we report as proof-of-concept the effective knockout of BDNF in subcutaneous adipose tissue after PA-Cre activation through external blue light illumination in awake, freely moving mice. We demonstrated that for mice with black fur, shaving can be used to anatomically limit PA-Cre activation. BDNF protein expression was decreased by 87% in the inguinal scWAT after blue light exposure, with no effect observed in the perigonadal (deep) or axillary subcutaneous (non-shaved) adipose tissues. We propose blue light induction of PA-Cre as safe and effective to study adipose tissue physiology and pathology across models. Considerations for applying this tool to future studies are also presented.

Keywords: BDNF; Optogenetics; adipose tissue; development; light-inducible Cre; obesity; photoactivatable (PA)-Cre; tissue knockout

DOI: https://doi.org/10.1080/21623945.2026.2671558