bims-mimcad 2024-11-24 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024–11–24
nine papers selected by
Henver Brunetta, Karolinska Institutet

Personalized phosphoproteomics of skeletal muscle insulin resistance and exercise links MINDY1 to insulin action.
Tirzepatide Reduces LV Mass and Paracardiac Adipose Tissue in Obesity-Related Heart Failure: SUMMIT CMR Substudy.
MOTS-c modulates skeletal muscle function by directly binding and activating CK2.
Dietary control of peripheral adipose storage capacity through membrane lipid remodelling.
Impaired branched chain amino acid (BCAA) catabolism during adipocyte differentiation decreases glycolytic flux.
Senescent Cell Depletion Alleviates Obesity-related Metabolic and Cardiac Disorders.
Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial.
Activation of the HPA axis does not explain non-responsiveness to GLP-1R agonist treatment in individuals with type 2 diabetes.
Effects of Tirzepatide on the Clinical Trajectory of Patients with Heart Failure, a Preserved Ejection Fraction, and Obesity.

Cell Metab. 2024 Nov 18. pii: S1550-4131(24)00416-9. [Epub ahead of print]

Personalized phosphoproteomics of skeletal muscle insulin resistance and exercise links MINDY1 to insulin action.

Elise J Needham, Janne R Hingst, Johan D Onslev, Alexis Diaz-Vegas, Magnus R Leandersson, Hannah Huckstep, Jonas M Kristensen, Kohei Kido, Erik A Richter, Kurt Højlund, Benjamin L Parker, Kristen Cooke, Guang Yang, Christian Pehmøller, Sean J Humphrey, David E James, Jørgen F P Wojtaszewski.

  Type 2 diabetes is preceded by a defective insulin response, yet our knowledge of the precise mechanisms is incomplete. Here, we investigate how insulin resistance alters skeletal muscle signaling and how exercise partially counteracts this effect. We measured parallel phenotypes and phosphoproteomes of insulin-resistant (IR) and insulin-sensitive (IS) men as they responded to exercise and insulin (n = 19, 114 biopsies), quantifying over 12,000 phosphopeptides in each biopsy. Insulin resistance involves selective and time-dependent alterations to signaling, including reduced insulin-stimulated mTORC1 and non-canonical signaling responses. Prior exercise promotes insulin sensitivity even in IR individuals by "priming" a portion of insulin signaling prior to insulin infusion. This includes MINDY1 S441, which we show is an AKT substrate. We found that MINDY1 knockdown enhances insulin-stimulated glucose uptake in rat myotubes. This work delineates the signaling alterations in IR skeletal muscle and identifies MINDY1 as a regulator of insulin action.

Keywords:  MINDY1; cell signaling; exercise; insulin; insulin resistance; phosphoproteomics; proteomics; skeletal muscle

DOI:  https://doi.org/10.1016/j.cmet.2024.10.020
J Am Coll Cardiol. 2024 Nov 05. pii: S0735-1097(24)10414-7. [Epub ahead of print]

Tirzepatide Reduces LV Mass and Paracardiac Adipose Tissue in Obesity-Related Heart Failure: SUMMIT CMR Substudy.

SUMMIT Trial Study Group

   BACKGROUND: Obesity is a known risk factor for heart failure with preserved ejection fraction (HFpEF) and is considered a distinct phenotype with more concentric remodeling. Epicardial adipose tissue (EAT) is also increased in obesity-related HFpEF and is associated with adverse events.
OBJECTIVE: The Cardiac Magnetic Resonance (CMR) Substudy of the SUMMIT trial was aimed to examine the effects of tirzepatide on cardiac structure and function with the underlying hypothesis that it would reduce left ventricular (LV) mass and EAT in obesity-related HFpEF.
METHODS: One hundred seventy-five patients with obesity-related HFpEF from the parent study of tirzepatide (2.5mg SQ weekly, increasing to a maximum of 15mg weekly) or matching placebo underwent CMR at baseline, which consisted of multiplanar cine imaging. One hundred six patients completed the CMR and had adequate image quality for analysis of LV and LA structure and function and paracardiac (epicardial plus pericardial) adipose tissue at both baseline and 52 weeks. The prespecified primary endpoint of this substudy was between-group changes in LV mass.
RESULTS: LV mass decreased by 11 g (95% C.I. -19 to -4) in the treated group (n = 50) when corrected for placebo (n =56) (p=0.004). Paracardiac adipose tissue decreased in the treated group by 45 ml (95% C.I. -69 to -22) when corrected for placebo (p<0.001). The change in LV mass in the treated group correlated with changes in body weight (p<0.02) and, tended to correlate with changes in waist circumference and blood pressure (p=0.06 for both). The LV mass change also correlated with changes in LV end diastolic volume and LA end diastolic and end systolic volumes (p<0.03 for all).
CONCLUSION: The CMR substudy of the SUMMIT trial demonstrated that tirzepatide therapy in obesity-related HFpEF led to reduced LV mass and paracardiac adipose tissue as compared to placebo and the change in LV mass paralleled weight loss. These physiologic changes may contribute to the reduction in heart failure events seen in the main SUMMIT trial.

Keywords:  GLP1 agonist; HFpEF; LV mass; cardiac MRI; obesity

DOI:  https://doi.org/10.1016/j.jacc.2024.11.001
iScience. 2024 Nov 15. 27(11): 111212

MOTS-c modulates skeletal muscle function by directly binding and activating CK2.

Hiroshi Kumagai, Su-Jeong Kim, Brendan Miller, Hirofumi Zempo, Kumpei Tanisawa, Toshiharu Natsume, Shin Hyung Lee, Junxiang Wan, Naphada Leelaprachakul, Michi Emma Kumagai, Ricardo Ramirez, Hemal H Mehta, Kevin Cao, Tae Jung Oh, James A Wohlschlegel, Jihui Sha, Yuichiro Nishida, Noriyuki Fuku, Shohei Dobashi, Eri Miyamoto-Mikami, Mizuki Takaragawa, Mizuho Fuku, Toshinori Yoshihara, Hisashi Naito, Ryoko Kawakami, Suguru Torii, Taishi Midorikawa, Koichiro Oka, Megumi Hara, Chiharu Iwasaka, Yosuke Yamada, Yasuki Higaki, Keitaro Tanaka, Kelvin Yen, Pinchas Cohen.

  MOTS-c is a mitochondrial microprotein that improves metabolism. Here, we demonstrate CK2 is a direct and functional target of MOTS-c. MOTS-c directly binds to CK2 and activates it in cell-free systems. MOTS-c administration to mice prevented skeletal muscle atrophy and enhanced muscle glucose uptake, which were blunted by suppressing CK2 activity. Interestingly, the effects of MOTS-c are tissue-specific. Systemically administered MOTS-c binds to CK2 in fat and muscle, yet stimulates CK2 activity in muscle while suppressing it in fat by differentially modifying CK2-interacting proteins. Notably, a naturally occurring MOTS-c variant, K14Q MOTS-c, has reduced binding to CK2 and does not activate it or elicit its effects. Male K14Q MOTS-c carriers exhibited a higher risk of sarcopenia and type 2 diabetes (T2D) in an age- and physical-activity-dependent manner, whereas females had an age-specific reduced risk of T2D. Altogether, these findings provide evidence that CK2 is required for MOTS-c effects.

Keywords:  Physiology; cell biology

DOI:  https://doi.org/10.1016/j.isci.2024.111212
bioRxiv. 2024 Oct 29. pii: 2024.10.25.620374. [Epub ahead of print]

Dietary control of peripheral adipose storage capacity through membrane lipid remodelling.

Marcus J Tol, Yuta Shimanaka, Alexander H Bedard, Jennifer Sapia, Liujuan Cui, Mariana Colaço-Gaspar, Peter Hofer, Alessandra Ferrari, Kevin Qian, John P Kennelly, Stephen D Lee, Yajing Gao, Xu Xiao, Jie Gao, Julia J Mack, Thomas A Weston, Calvin Pan, Aldons J Lusis, Kevin J Williams, Baolong Su, Daniel P Pike, Alex Reed, Natalia Milosevich, Benjamin F Cravatt, Makoto Arita, Stephen G Young, David A Ford, Rudolf Zechner, Stefano Vanni, Peter Tontonoz.

Complex genetic and dietary cues contribute to the development of obesity, but how these are integrated on a molecular level is incompletely understood. Here, we show that PPARγ supports hypertrophic expansion of adipose tissue via transcriptional control of LPCAT3, a membrane-bound O-acyltransferase that enriches diet-derived omega-6 ( n -6) polyunsaturated fatty acids (PUFAs) in the phospholipidome. In high-fat diet-fed mice, lowering membrane n -6 PUFA levels by adipocyte-specific Lpcat3 knockout ( Lpcat3 AKO ) or by dietary lipid manipulation leads to dysfunctional triglyceride (TG) storage, ectopic fat deposition and insulin resistance. Aberrant lipolysis of stored TGs in Lpcat3 AKO adipose tissues instigates a non-canonical adaptive response that engages a futile lipid cycle to increase energy expenditure and limit further body weight gain. Mechanistically, we find that adipocyte LPCAT3 activity promotes TG storage by selectively enriching n -6 arachidonoyl-phosphatidylethanolamine at the ER-lipid droplet interface, which in turn favours the budding of large droplets that exhibit greater resistance to ATGL-dependent hydrolysis. Thus, our study highlights the PPARγ-LPCAT3 pathway as a molecular link between dietary n -6 PUFA intake, adipose expandability and systemic energy balance.

DOI: https://doi.org/10.1101/2024.10.25.620374
J Biol Chem. 2024 Nov 15. pii: S0021-9258(24)02506-7. [Epub ahead of print] 108004

Impaired branched chain amino acid (BCAA) catabolism during adipocyte differentiation decreases glycolytic flux.

Courtney R Green, Lynn M Alaeddine, Karl A Wessendorf-Rodriguez, Rory Turner, Merve Elmastas, Justin D Hover, Anne N Murphy, Mikael Ryden, Niklas Mejhert, Christian M Metallo, Martina Wallace.

  Dysregulated branched chain amino acid (BCAA) metabolism has emerged as a key metabolic feature associated with the obese insulin resistant state, and adipose BCAA catabolism is decreased in this context. BCAA catabolism is upregulated early in adipogenesis, but the impact of suppressing this pathway on the broader metabolic functions of the resultant adipocyte remains unclear. Here, we use CRISPR/Cas9 to decrease BCKDHA in 3T3-L1 and human pre-adipocytes, and ACAD8 in 3T3-L1 pre-adipocytes to induce a deficiency in BCAA catabolism through differentiation. We characterize the transcriptional and metabolic phenotype of 3T1-L1 cells using RNAseq and 13C metabolic flux analysis within a network spanning glycolysis, tricarboxylic acid (TCA) metabolism, BCAA catabolism, and fatty acid synthesis. While lipid droplet accumulation is maintained in Bckdha-deficient adipocytes, they display a more fibroblast-like transcriptional signature. In contrast, Acad8 deficiency minimally impacts gene expression. Decreased glycolytic flux emerges as the most distinct metabolic feature of 3T3-L1 Bckdha-deficient cells, accompanied by a ∼40% decrease in lactate secretion, yet pyruvate oxidation and utilization for de novo lipogenesis are increased to compensate for loss of BCAA carbon. Deletion of BCKDHA in human adipocyte progenitors also led to a decrease in glucose uptake and lactate secretion, however these cells did not upregulate pyruvate utilisation and lipid droplet accumulation and expression of adipocyte differentiation markers was decreased in BCKDH knockout cells. Overall our data suggest that human adipocyte differentiation may be more sensitive to the impact of decreased BCKDH activity than 3T3-L1 cells, and that both metabolic and regulatory cross-talk exists between BCAA catabolism and glycolysis in adipocytes. Suppression of BCAA catabolism associated with metabolic syndrome may result in a metabolically compromised adipocyte.

Keywords:  adipogenesis; adipose; branched chain amino acids; glycolysis; metabolic flux

DOI:  https://doi.org/10.1016/j.jbc.2024.108004
Mol Metab. 2024 Nov 16. pii: S2212-8778(24)00196-0. [Epub ahead of print] 102065

Senescent Cell Depletion Alleviates Obesity-related Metabolic and Cardiac Disorders.

Tábatha de Oliveira Silva, Guilherme Lunardon, Caroline A Lino, Amanda de Almeida Silva, Shiju Zhang, Maria Cláudia Costa Irigoyen, Yao Wei Lu, John D Mably, Maria Luiza M Barreto-Chaves, Da-Zhi Wang, Gabriela P Diniz.

  Obesity is a major contributor to metabolic and cardiovascular disease. Although senescent cells have been shown to accumulate in adipose tissue, the role of senescence in obesity-induced metabolic disorders and in cardiac dysfunction is not yet clear; therefore, the therapeutic potential of managing senescence in obesity-related metabolic and cardiac disorders remains to be fully defined. We investigated the beneficial effects of a senolytic cocktail (dasatinib and quercetin) on senescence and its influence on obesity-related parameters. We found that the increase in body weight and adiposity, glucose intolerance, insulin resistance, dyslipidemia, hyperleptinemia, and hepatic disorders which were induced by an obesogenic diet were alleviated by senolytic cocktail treatment in mice. Treatment with senolytic compounds eliminated senescent cells, counteracting the activation of the senescence program and DNA damage in white adipose tissue (WAT) observed with an obesogenic diet. Moreover, the senolytic cocktail prevented the brown adipose tissue (BAT) whitening and increased the expression of the thermogenic gene profile in BAT and pWAT. In the hearts of obese mice, senolytic combination abolished myocardial maladaptation, reducing the senescence-associated secretory phenotype (SASP) and DNA damage, repressing cardiac hypertrophy, and improving diastolic dysfunction. Additionally, we showed that treatment with the senolytic cocktail corrected gene expression programs associated with fatty acid metabolism, oxidative phosphorylation, the P53 pathway, and DNA repair, which were all downregulated in obese mice. Collectively, these data suggest that a senolytic cocktail can prevent the activation of the senescence program in the heart and WAT and activate the thermogenic program in BAT. Our results suggest that targeting senescent cells may be a novel therapeutic strategy for alleviating obesity-related metabolic and cardiac disorders.

Keywords:  brown adipose tissue; cardiac dysfunction; cellular senescence; metabolic dysfunction; obesity

DOI:  https://doi.org/10.1016/j.molmet.2024.102065
Nat Med. 2024 Nov 17.

Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial.

Barry A Borlaug, Michael R Zile, Christopher M Kramer, Seth J Baum, Karla Hurt, Sheldon E Litwin, Masahiro Murakami, Yang Ou, Navneet Upadhyay, Milton Packer.

Patients with obesity-related heart failure with preserved ejection fraction (HFpEF) display circulatory volume expansion and pressure overload contributing to cardiovascular-kidney end-organ damage. In the SUMMIT trial, patients with HFpEF and obesity were randomized to the long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist tirzepatide (n = 364, 200 women) or placebo (n = 367, 193 women). As reported separately, tirzepatide decreased cardiovascular death or worsening heart failure. Here, in this mechanistic secondary analysis of the SUMMIT trial, tirzepatide treatment at 52 weeks, as compared with placebo, reduced systolic blood pressure (estimated treatment difference (ETD) -5 mmHg, 95% confidence interval (CI) -7 to -3; P < 0.001), decreased estimated blood volume (ETD -0.58 l, 95% CI -0.63 to -0.52; P < 0.001) and reduced C-reactive protein levels (ETD -37.2%, 95% CI -45.7 to -27.3; P < 0.001). These changes were coupled with an increase in estimated glomerular filtration rate (ETD 2.90 ml min-1 1.73 m-2 yr-1, 95% CI 0.94 to 4.86; P = 0.004), a decrease in urine albumin-creatinine ratio (ETD 24 weeks, -25.0%, 95% CI -36 to -13%; P < 0.001; 52 weeks, -15%, 95% CI -28 to 0.1; P = 0.051), a reduction in N-terminal prohormone B-type natriuretic peptide levels (ETD 52 weeks -10.5%, 95% CI -20.7 to 1.0%; P = 0.07) and a reduction in troponin T levels (ETD 52 weeks -10.4%, 95% CI -16.7 to -3.6; P = 0.003). In post hoc exploratory analyses, decreased estimated blood volume with tirzepatide treatment was significantly correlated with decreased blood pressure, reduced microalbuminuria, improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and increased 6-min walk distance. Moreover, decreased C-reactive protein levels were correlated with reduced troponin T levels and improved 6-min walk distance. In conclusion, tirzepatide reduced circulatory volume-pressure overload and systemic inflammation and mitigated cardiovascular-kidney end-organ injury in patients with HFpEF and obesity, providing new insights into the mechanisms of benefit from tirzepatide. ClinicalTrials.gov registration: NCT04847557 .

DOI: https://doi.org/10.1038/s41591-024-03374-z
Diabetes. 2024 Nov 19. pii: db240463. [Epub ahead of print]

Activation of the HPA axis does not explain non-responsiveness to GLP-1R agonist treatment in individuals with type 2 diabetes.

Sevilay Tokgöz, Marti Boss, Theodorus Jp Jansen, Rick Meijer, Cathelijne Frielink, Arianne C van Bon, Cees J Tack, Bastiaan E de Galan, Martin Gotthardt.

Glucagon-like peptide 1 receptor (GLP-1R) agonists fail to reduce weight and improve glucose control in a sizable minority of people with type 2 diabetes. We hypothesized that stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by GLP-1R agonists, thus inducing cortisol secretion, could explain this unresponsiveness to GLP-1R agonists. To assess the effects of GLP-1R agonist treatment on the HPA axis, we selected ten individuals with type 2 diabetes with (5 women/5 men) and nine without (4 women/5 men) an adequate response to GLP-1R agonists and used [68Ga]Ga-NODAGA-exendin-4 positron emission tomography (PET)/computed tomography (CT) to quantify GLP-1R expression in the pituitary. Oral glucose tolerance and 24 h urinary cortisol excretion was measured in all participants. Pituitary tracer uptake was observed in all participants with no significant difference between responders and non-responders. Pituitary tracer uptake correlated with the area under the curve for ACTH, urinary cortisol to creatinine ratio and age. Interestingly, men had higher pituitary tracer uptake than women. In conclusion, this study does not indicate a role for pituitary GLP-1R expression and HPA axis stimulation to explain the difference in treatment response to GLP-1R agonists among individuals with type 2 diabetes. The findings of substantial pituitary GLP-1R expression and the significant sex differences require further research.

DOI: https://doi.org/10.2337/db24-0463
Circulation. 2024 Nov 18.

Effects of Tirzepatide on the Clinical Trajectory of Patients with Heart Failure, a Preserved Ejection Fraction, and Obesity.

SUMMIT Trial Study Group

BACKGROUND: Patients with heart failure, a preserved ejection fraction (HFpEF), and obesity have significant disability and suffer frequent exacerbations of heart failure. We hypothesized that tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, would improve a comprehensive suite of clinical endpoints, including measures of health status, functional capacity, quality of life, exercise tolerance, patient well-being, and medication burden in these patients.
METHODS: 731 patients in class II-IV heart failure, ejection fraction ≥50%, and body mass index ≥30 kg/m2 were randomized(double-blind) to tirzepatide(titrated up to 15mg subcutaneously weekly)(n=364) or placebo(n=367), added to background therapy for a median of 104 weeks (Q1=66, Q3=126 weeks).
PRIMARY ENDPOINTS: tirzepatide reduced the combined risk of cardiovascular death or worsening heart failure and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score(KCCQ-CSS). The current expanded analysis included sensitivity analyses of the primary endpoints, 6-minute walk distance(6MWD), EQ-5D-5L health state index, Patient Global Impression of Severity Overall Health(PGIS), NYHA class, use of heart failure medications, and a hierarchical composite based on all-cause death, worsening heart failure, and 52-week changes in KCCQ-CSS and 6MWD.
RESULTS: Patients were aged 65.2±10.7, 53.8%(n=393) were female; BMI 38.2±6.7kg/m2, KCCQ-CSS 53.5±18.5, 6MWD 302.8±81.7meters, and 53%(n=388) had a worsening heart failure event in the prior 12 months. Compared with placebo, tirzepatide produced a consistent beneficial effect across all composites of death and worsening heart failure events, analyzed as time-to-first-event (hazard ratios 0.41-0.67). At 52 weeks, tirzepatide increased KCCQ-CSS 6.9 points (95%CI, 3.3, 10.6, P<0.001), 6MWD 18.3 meters (95%CI, 9.9, 26.7, P<0.001) and EQ-5D-5L 0.06 (95%CI, 0.03, 0.09, P<0.001). The tirzepatide group shifted to a more favorable PGIS (proportional odds ratio 1.99 (95%CI, 1.44, 2.76) and NYHA class (proportional odds ratio 2.26 (95%CI, 1.54, 3.31), both P<0.001 and required less heart failure medications (P=0.015). The broad spectrum of effects was reflected in benefits on the hierarchical composite (win ratio 1.63, 95%CI, 1.17, 2.28;P=0.004).
CONCLUSIONS: Tirzepatide produced a comprehensive, meaningful improvement in heart failure across multiple complementary domains; enhanced health status, quality of life, functional capacity, exercise tolerance and well-being; and reduced symptoms and medication burden in patients with HFpEF and obesity.

DOI: https://doi.org/10.1161/CIRCULATIONAHA.124.072679