bims-mimcad 2024-04-14 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024–04–14
twelve papers selected by
Henver Brunetta, University of Guelph

Adipose tissue macrophages secrete small extracellular vesicles that mediate rosiglitazone-induced insulin sensitization.
Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.
Myocardial Metabolism in Heart Failure with Preserved Ejection Fraction.
Semaglutide-a new treatment for obesity-related heart failure with preserved ejection fraction?
Depletion of TBC1D4 improves the metabolic exercise response by overcoming genetically induced peripheral insulin resistance.
Insulin regulation of regional lipolysis in upper-body obese and lean humans.
Body composition and body fat distribution in tissue-specific insulin resistance and in response to a 12-week isocaloric dietary macronutrient intervention.
Impact of sustained calorie restriction and weight cycling on body composition in high-fat diet-fed male and female C57BL/6J mice.
Epicardial and intra-thoracic adipose tissue and cardiovascular calcifications in type 1 diabetes (T1D) in epidemiology of diabetes Interventions and Complications (EDIC): A pilot study.
Krüppel-like factor 10 protects against metabolic dysfunction-associated steatohepatitis by regulating HNF4α-mediated metabolic pathways.
Paternal dietary macronutrient balance and energy intake drive metabolic and behavioral differences among offspring.
Pharmacological activation of PDC flux reverses lipid-induced inhibition of insulin action in muscle during recovery from exercise.

Nat Metab. 2024 Apr 11.

Adipose tissue macrophages secrete small extracellular vesicles that mediate rosiglitazone-induced insulin sensitization.

Theresa V Rohm, Felipe Castellani Gomes Dos Reis, Roi Isaac, Cairo Murphy, Karina Cunha E Rocha, Gautam Bandyopadhyay, Hong Gao, Avraham M Libster, Rizaldy C Zapata, Yun Sok Lee, Wei Ying, Charlene Miciano, Allen Wang, Jerrold M Olefsky.

The obesity epidemic continues to worsen worldwide, driving metabolic and chronic inflammatory diseases. Thiazolidinediones, such as rosiglitazone (Rosi), are PPARγ agonists that promote 'M2-like' adipose tissue macrophage (ATM) polarization and cause insulin sensitization. As ATM-derived small extracellular vesicles (ATM-sEVs) from lean mice are known to increase insulin sensitivity, we assessed the metabolic effects of ATM-sEVs from Rosi-treated obese male mice (Rosi-ATM-sEVs). Here we show that Rosi leads to improved glucose and insulin tolerance, transcriptional repolarization of ATMs and increased sEV secretion. Administration of Rosi-ATM-sEVs rescues obesity-induced glucose intolerance and insulin sensitivity in vivo without the known thiazolidinedione-induced adverse effects of weight gain or haemodilution. Rosi-ATM-sEVs directly increase insulin sensitivity in adipocytes, myotubes and primary mouse and human hepatocytes. Additionally, we demonstrate that the miRNAs within Rosi-ATM-sEVs, primarily miR-690, are responsible for these beneficial metabolic effects. Thus, using ATM-sEVs with specific miRNAs may provide a therapeutic path to induce insulin sensitization.

DOI: https://doi.org/10.1038/s42255-024-01023-w
bioRxiv. 2024 Mar 29. pii: 2024.03.26.586781. [Epub ahead of print]

Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.

Dylan C Sarver, Muzna Saqib, Fangluo Chen, G William Wong.

Organ function declines with age, and large-scale transcriptomic analyses have highlighted differential aging trajectories across tissues. The mechanisms underlying shared and organ-selective functional changes across the lifespan, however, still remains poorly understood. Given the central role of mitochondria in powering cellular processes needed to maintain tissue health, we therefore undertook a systematic assessment of respiratory activity across 33 different tissues in young (2.5 months) and old (20 months) mice of both sexes. Our high-resolution mitochondrial respiration atlas reveals: 1) within any group of mice, mitochondrial activity varies widely across tissues, with the highest values consistently seen in heart, brown fat, and kidney; 2) biological sex is a significant but minor contributor to mitochondrial respiration, and its contributions are tissue-specific, with major differences seen in the pancreas, stomach, and white adipose tissue; 3) age is a dominant factor affecting mitochondrial activity, especially across different fat depots and skeletal muscle groups, and most brain regions; 4) age-effects can be sex- and tissue-specific, with some of the largest effects seen in pancreas, heart, adipose tissue, and skeletal muscle; and 5) while aging alters the functional trajectories of mitochondria in a majority of tissues, some are remarkably resilient to age-induced changes. Altogether, our data provide the most comprehensive compendium of mitochondrial respiration and illuminate functional signatures of aging across diverse tissues and organ systems.

DOI: https://doi.org/10.1101/2024.03.26.586781
J Clin Med. 2024 Feb 20. pii: 1195. [Epub ahead of print]13(5):

Myocardial Metabolism in Heart Failure with Preserved Ejection Fraction.

John Aaron Henry, Liam S Couch, Oliver J Rider.

  Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent and now accounts for half of all heart failure cases. This rise is largely attributed to growing rates of obesity, hypertension, and diabetes. Despite its prevalence, the pathophysiological mechanisms of HFpEF are not fully understood. The heart, being the most energy-demanding organ, appears to have a compromised bioenergetic capacity in heart failure, affecting all phenotypes and aetiologies. While metabolic disturbances in heart failure with reduced ejection fraction (HFrEF) have been extensively studied, similar insights into HFpEF are limited. This review collates evidence from both animal and human studies, highlighting metabolic dysregulations associated with HFpEF and its risk factors, such as obesity, hypertension, and diabetes. We discuss how changes in substrate utilisation, oxidative phosphorylation, and energy transport contribute to HFpEF. By delving into these pathological shifts in myocardial energy production, we aim to reveal novel therapeutic opportunities. Potential strategies include modulating energy substrates, improving metabolic efficiency, and enhancing critical metabolic pathways. Understanding these aspects could be key to developing more effective treatments for HFpEF.

Keywords:  HFpEF; cardiac metabolism; energy production; heart failure; substrate utilisation

DOI:  https://doi.org/10.3390/jcm13051195
Lancet. 2024 Apr 04. pii: S0140-6736(24)00653-6. [Epub ahead of print]

Semaglutide-a new treatment for obesity-related heart failure with preserved ejection fraction?

Erwan Donal, Guillaume L'Official, Sabina Istratoaie.

DOI: https://doi.org/10.1016/S0140-6736(24)00653-6
Diabetes. 2024 Apr 12. pii: db230463. [Epub ahead of print]

Depletion of TBC1D4 improves the metabolic exercise response by overcoming genetically induced peripheral insulin resistance.

Christian Springer, Christian Binsch, Deborah Weide, Laura Toska, Anna Lena Cremer, Heiko Backes, Anna K Scheel, Lena Espelage, Jörg Kotzka, Sebastian Sill, Anette Kurowski, Daebin Kim, Sandra Karpinski, Theresia M Schnurr, Torben Hansen, Sonja Hartwig, Stefan Lehr, Sandra Cames, Jens Brüning, Matthias Lienhard, Ralf Herwig, Stefan Börno, Bernd Timmermann, Hadi Al-Hasani, Alexandra Chadt.

The RabGTPase-activating protein (RabGAP) TBC1D4 (=AS160) represents a key component in the regulation of glucose transport into skeletal muscle and white adipose tissue (WAT) and is therefore crucial during the development of insulin resistance and type-2 diabetes. Increased daily activity has been shown to be associated with improved postprandial hyperglycemia in allele carriers of a loss-of-function variant in the human TBC1D4 gene. Using conventional Tbc1d4-deficient mice (D4KO) fed a high-fat diet (HFD), we show that already a moderate endurance exercise training leads to substantially improved glucose and insulin tolerance and enhanced expression levels of markers for mitochondrial activity and browning in WAT from D4KO animals. Importantly, in vivo and ex vivo analyses of glucose uptake revealed increased glucose clearance in interscapular brown adipose tissue (iBAT) and WAT from trained D4KO mice. Thus, chronic exercise is able to overcome the genetically induced insulin resistance caused by the Tbc1d4-depletion. Gene variants in TBC1D4 may be relevant in future precision medicine as determinants of exercise response.

DOI: https://doi.org/10.2337/db23-0463
JCI Insight. 2024 Apr 11. pii: e175629. [Epub ahead of print]

Insulin regulation of regional lipolysis in upper-body obese and lean humans.

Søren Nielsen, Michael D Jensen.

   BACKGROUND: Upper body obesity (UBO) results in insulin resistance with regards to free fatty acid (FFA) release; how this differs by fat depot and sex between UBO and lean adults is unknown. We tested the hypothesis that insulin suppression of FFA release from the splanchnic bed, leg fat and upper body non-splanchnic (UBNS) adipose tissue would be impaired in UBO.
METHODS: Fourteen UBO (7 men, 7 women) and 14 healthy, normal weight (7 men, 7 women) volunteers participated in studies that included femoral artery, femoral vein and hepatic vein catheterization. We then measured leg and splanchnic plasma flow as well as FFA kinetics (using isotopic tracers) under overnight fasting, low- and high-dose insulin infusion using the insulin clamp technique.
RESULTS: We found the expected insulin resistance in UBO; the most quantitatively important difference between UBO and lean adults was greater FFA release from UBNS adipose tissue when plasma insulin concentrations are in the post-prandial, physiological range. There were obesity, but not sex differences in the regulation of splanchnic FFA release and sex differences in the regulation of leg FFA release.
CONCLUSION: Reversing the defects in insulin-regulated UBNS adipose tissue FFA release would have the greatest impact on systemic FFA abnormalities in UBO.
TRIAL REGISTRATION: (not applicable)Funding: These studies were supported by grants DK45343 and DK40484 from the U.S. Public Health Service, and the Novo Nordic Foundation (grant numbers NNF18OC0031804 and NNF16OC0021406) and the Independent Research Fund Denmark (grant number 8020-00420B).

Keywords:  Adipose tissue; Endocrinology; Insulin; Obesity

DOI:  https://doi.org/10.1172/jci.insight.175629
Nutr Metab (Lond). 2024 Apr 09. 21(1): 20

Body composition and body fat distribution in tissue-specific insulin resistance and in response to a 12-week isocaloric dietary macronutrient intervention.

Inez Trouwborst, Kelly M Jardon, Anouk Gijbels, Gabby Hul, Edith J M Feskens, Lydia A Afman, Jennifer Linge, Gijs H Goossens, Ellen E Blaak.

   BACKGROUND: Body composition and body fat distribution are important predictors of cardiometabolic diseases. The etiology of cardiometabolic diseases is heterogenous, and partly driven by inter-individual differences in tissue-specific insulin sensitivity.
OBJECTIVES: To investigate (1) the associations between body composition and whole-body, liver and muscle insulin sensitivity, and (2) changes in body composition and insulin sensitivity and their relationship after a 12-week isocaloric diet high in mono-unsaturated fatty acids (HMUFA) or a low-fat, high-protein, high-fiber (LFHP) diet.
METHODS: This subcohort analysis of the PERSON study includes 93 individuals (53% women, BMI 25-40 kg/m2, 40-75 years) who participated in this randomized intervention study. At baseline and after 12 weeks of following the LFHP, or HMUFA diet, we performed a 7-point oral glucose tolerance test to assess whole-body, liver, and muscle insulin sensitivity, and whole-body magnetic resonance imaging to determine body composition and body fat distribution. Both diets are within the guidelines of healthy nutrition.
RESULTS: At baseline, liver fat content was associated with worse liver insulin sensitivity (β [95%CI]; 0.12 [0.01; 0.22]). Only in women, thigh muscle fat content was inversely related to muscle insulin sensitivity (-0.27 [-0.48; -0.05]). Visceral adipose tissue (VAT) was inversely associated with whole-body, liver, and muscle insulin sensitivity. Both diets decreased VAT, abdominal subcutaneous adipose tissue (aSAT), and liver fat, but not whole-body and tissue-specific insulin sensitivity with no differences between diets. Waist circumference, however, decreased more following the LFHP diet as compared to the HMUFA diet (-3.0 vs. -0.5 cm, respectively). After the LFHP but not HMUFA diet, improvements in body composition were positively associated with improvements in whole-body and liver insulin sensitivity.
CONCLUSIONS: Liver and muscle insulin sensitivity are distinctly associated with liver and muscle fat accumulation. Although both LFHP and HMUFA diets improved in body fat, VAT, aSAT, and liver fat, only LFHP-induced improvements in body composition are associated with improved insulin sensitivity.
TRIAL REGISTRATION: NCT03708419 (clinicaltrials.gov).

Keywords:  Body composition; Body fat distribution; Dietary intervention; Isocaloric; Whole-body MRI; Whole-body and tissue-specific insulin resistance

DOI:  https://doi.org/10.1186/s12986-024-00795-y
Obesity (Silver Spring). 2024 Apr 10.

Impact of sustained calorie restriction and weight cycling on body composition in high-fat diet-fed male and female C57BL/6J mice.

Daniel L Smith, Yongbin Yang, Luis M Mestre, Beate Henschel, Erik Parker, Stephanie Dickinson, Amit Patki, David B Allison, Tim R Nagy.

OBJECTIVE: The objective of this study was to investigate body composition changes with weight cycling (WC) among adult C57BL/6J mice with diet-induced obesity.
METHODS: A total of 555 single-housed mice were fed a high-fat diet ad libitum (AL) from 8 to 43 weeks of age. The 200 heaviest mice of each sex were randomized to the following four groups: ever obese (EO, continued AL feeding); obese weight loser (OWL, calorie-restricted); obese weight loser moderate (OWLM, body weight halfway between EO and OWL); and WC (diet restricted to OWL followed by AL refeeding cycles). Body weight and composition data were collected. Linear regression was used to calculate residuals between predicted and observed fat mass. Linear mixed models were used to compare diet groups.
RESULTS: Although weight loss and regain resulted in changes in body weight and composition, fat mass, body weight, and relative body fat were not significantly greater for the WC group compared with the EO group. During long-term calorie restriction, males (but not females) in the OWLM group remained relatively fatter than the EO group.
CONCLUSIONS: WC did not increase body weight or relative fat mass for middle-aged, high-fat diet-fed adult mice. However, long-term moderate calorie restriction resulted in lower body weight but greater "relative" fat in male mice.

DOI: https://doi.org/10.1002/oby.24015
Am J Prev Cardiol. 2024 Jun;18 100650

Epicardial and intra-thoracic adipose tissue and cardiovascular calcifications in type 1 diabetes (T1D) in epidemiology of diabetes Interventions and Complications (EDIC): A pilot study.

DCCT/EDIC Research Group

   Objective: Coronary artery, aortic valve, and descending aorta calcification (CAC, AVC, DAC) are manifestations of atherosclerosis, and cardiac epicardial adipose tissue (EAT) indicates heart adiposity. This study explored the association between cardiac adipose tissue and cardiovascular calcification in participants with long-standing T1D.
Methods: EAT and intra-thoracic adipose tissue (IAT) were measured in 100 T1D subjects with cardiac computed tomography (CT) scans in the EDIC study. Volume analysis software was used to measure fat volumes. Spearman correlations were calculated between CAC, AVC, DAC with EAT, and IAT. Associations were evaluated using multiple linear and logistic regression models.
Results: Participants ranged in age from 32 to 57. Mean EAT, and IAT were 38.5 and 50.8 mm3, respectively, and the prevalence of CAC, AVC, and DAC was 43.6 %, 4.7 %, and 26.8 %, respectively. CAC was positively correlated with age (p-value = 0.0001) and EAT (p-value = 0.0149) but not with AVC and DAC; IAT was not associated with calcified lesions. In models adjusted for age and sex, higher levels of EAT and IAT were associated with higher CAC (p-value < 0.0001 for both) and higher AVC (p-values of 0.0111 and 0.0053, respectively), but not with DAC. The associations with CAC remained significant (p-value < 0.0001) after further adjustment for smoking, systolic blood pressure, BMI, and LDL, while the associations with AVC did not remain significant.
Conclusion: In participants with T1D, higher EAT and IAT levels are correlated with higher CAC scores. EAT and IAT were not independently correlated with DAC or AVC.

Keywords:  Adipose tissue; Calcification; Coronary; Epicardial; Intra-thoracic; Type 1 Diabtes Melitus

DOI:  https://doi.org/10.1016/j.ajpc.2024.100650
Metabolism. 2024 Apr 04. pii: S0026-0495(24)00135-5. [Epub ahead of print]155 155909

Krüppel-like factor 10 protects against metabolic dysfunction-associated steatohepatitis by regulating HNF4α-mediated metabolic pathways.

Xiaoli Pan, Shuwei Hu, Yanyong Xu, Raja Gopoju, Yingdong Zhu, Fathima N Cassim Bawa, Hui Wang, Jiayou Wang, Zaid Batayneh, Alyssa Clark, Yuhao Zeng, Li Lin, Xinwen Wang, Liya Yin, Yanqiao Zhang.

   BACKGROUND: Krüppel-like factor 10 (KLF10), a zinc finger transcription factor, plays a pivotal role in modulating TGF-β-mediated cellular processes such as growth, apoptosis, and differentiation. Recent studies have implicated KLF10 in regulating lipid metabolism and glucose homeostasis. This study aimed to elucidate the precise role of hepatic KLF10 in developing metabolic dysfunction-associated steatohepatitis (MASH) in diet-induced obese mice.
METHODS: We investigated hepatic KLF10 expression under metabolic stress and the effects of overexpression or ablation of hepatic KLF10 on MASH development and lipidemia. We also determined whether hepatocyte nuclear factor 4α (HNF4α) mediated the metabolic effects of KLF10.
RESULTS: Hepatic KLF10 was downregulated in MASH patients and genetically or diet-induced obese mice. AAV8-mediated overexpression of KLF10 in hepatocytes prevented Western diet-induced hypercholesterolemia and steatohepatitis, whereas inactivation of hepatocyte KLF10 aggravated Western diet-induced steatohepatitis. Mechanistically, KLF10 reduced hepatic triglyceride and free fatty acid levels by inducing lipolysis and fatty acid oxidation and inhibiting lipogenesis, and reducing hepatic cholesterol levels by promoting bile acid synthesis. KLF10 highly induced HNF4α expression by directly binding to its promoter. The beneficial effect of KLF10 on MASH development was abolished in mice lacking hepatocyte HNF4α. In addition, the inactivation of KLF10 in hepatic stellate cells exacerbated Western diet-induced liver fibrosis by activating the TGF-β/SMAD2/3 pathway.
CONCLUSIONS: Our data collectively suggest that the transcription factor KLF10 plays a hepatoprotective role in MASH development by inducing HNF4α. Targeting hepatic KLF10 may offer a promising strategy for treating MASH.

Keywords:  Bile acid; Cholesterol metabolism; HNF4α; KLF10; MASH

DOI:  https://doi.org/10.1016/j.metabol.2024.155909
Nat Commun. 2024 Apr 06. 15(1): 2982

Paternal dietary macronutrient balance and energy intake drive metabolic and behavioral differences among offspring.

Angela Jane Crean, Alistair McNair Senior, Therese Freire, Thomas Daniel Clark, Flora Mackay, Gracie Austin, Tamara Jayne Pulpitel, Marcelo Aguiar Nobrega, Romain Barrès, Stephen James Simpson.

Paternal diet can influence the phenotype of the next generation, yet, the dietary components inducing specific responses in the offspring are not identified. Here, we use the Nutritional Geometry Framework to determine the effects of pre-conception paternal dietary macronutrient balance on offspring metabolic and behavioral traits in mice. Ten isocaloric diets varying in the relative proportion of protein, fats, and carbohydrates are fed to male mice prior to mating. Dams and offspring are fed standard chow and never exposed to treatment diets. Body fat in female offspring is positively associated with the paternal consumption of fat, while in male offspring, an anxiety-like phenotype is associated to paternal diets low in protein and high in carbohydrates. Our study uncovers that the nature and the magnitude of paternal effects are driven by interactions between macronutrient balance and energy intake and are not solely the result of over- or undernutrition.

DOI: https://doi.org/10.1038/s41467-024-46782-y
Diabetes. 2024 Apr 12. pii: db230879. [Epub ahead of print]

Pharmacological activation of PDC flux reverses lipid-induced inhibition of insulin action in muscle during recovery from exercise.

Christian S Carl, Marie M Jensen, Kim A Sjøberg, Dumitru Constantin-Teodosiu, Ian R Hill, Rasmus Kjøbsted, Paul L Greenhaff, Jørgen F P Wojtaszewski, Erik A Richter, Andreas M Fritzen, Bente Kiens.

Insulin resistance is a risk factor for type 2 diabetes and exercise can improve insulin sensitivity. However, following exercise high circulating fatty acid (FA) levels might counteract this. We hypothesized that such inhibition would be reduced by forcibly increasing carbohydrate oxidation through pharmacological activation of the pyruvate dehydrogenase complex (PDC). Insulin-stimulated glucose uptake was examined with a cross-over design in healthy young men (n = 8) in a previously exercised and a rested leg during a hyperinsulinemiceuglycemic clamp five hours after one-legged exercise with: 1) infusion of saline, 2) infusion of intralipid imitating circulating FA levels during recovery from whole-body exercise, and 3) infusion of intralipid + oral PDC-activator, dichloroacetate (DCA). Intralipid infusion reduced insulin-stimulated glucose uptake by 19% in the previously exercised leg, which was not observed in the contralateral rested leg. Interestingly, this effect of intralipid in the exercised leg was abolished by DCA, which increased muscle PDC activity (130%) and flux (acetylcarnitine 130%) and decreased inhibitory phosphorylation of PDC on Ser293 (∼40%) and Ser300 (∼80%). Novel insight is provided into the regulatory interaction between glucose and lipid metabolism during exercise recovery. Coupling exercise and PDC flux activation upregulated the capacity for both glucose transport (exercise) and oxidation (DCA), which seems necessary to fully stimulate insulin-stimulated glucose uptake during recovery.

DOI: https://doi.org/10.2337/db23-0879