Nutrition & Metabolism[JOURNAL]
Sun
200 papers
Response to letter by Muralidhar and Madhivanan: Clarity and quality assessment of epidemiology of sarcopenia: Prevalence, risk factors, and consequences.
Yuan S, Larsson SC
Metabolism · 2023 Jul · PMID 37068602 · Publisher ↗
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Hepatic IDH2 regulates glycolysis and gluconeogenesis.
Wang H, Xiong Q, He G … +12 more , Tang J, Sun L, Cheng S, Ke M, Chen S, Hu Y, Feng J, Song L, Tong B, Zhang Z, Dai Z, Xu Y
Metabolism · 2023 Jun · PMID 37044373 · Publisher ↗
BACKGROUND AND AIMS: The liver plays a central role in controlling glucose and lipid metabolism. IDH2, a mitochondrial protein, controls TCA cycle flux. However, its role in regulating metabolism in obesity is still uncl...
BACKGROUND AND AIMS: The liver plays a central role in controlling glucose and lipid metabolism. IDH2, a mitochondrial protein, controls TCA cycle flux. However, its role in regulating metabolism in obesity is still unclear. This study intends to investigate the impact of hepatic IDH2 expression on overnutrition-regulated glucose and lipid metabolism. METHODS: Hepatic IDH2 was knocked-out in mice by the approach of CRISPR-Cas9. Mice were subjected to starvation and refeeding for hepatic glucose and lipid studies in vivo. Primary hepatocytes and mouse normal liver cell line, AML12 cells were used for experiments in vitro. RESULTS: This study found that IDH2 protein levels were elevated in the livers of obese people and mice with high-fat diet consumption or hepatic steatosis. Liver IDH2-deletion mice (IDH2) were resistant to high-fat diet-induced body weight gain, with lower serum glucose and TG levels, increased insulin sensitivity, and higher FGF21 secretion, despite the higher TG content in the liver. Consistently, overexpression of IDH2 in hepatocytes promoted gluconeogenesis and enhanced glycogenesis. By performing mass spectrometry and proteomics analyses, we further demonstrated that IDH2-deficiency in hepatocytes accelerated ATP production by increasing forward TCA cycle flux, thus promoting glycolysis pathway and decreasing glycogen synthesis at refeeding state, and inhibiting hepatic gluconeogenesis, increasing β-oxidation during starvation. Moreover, experiments in vivo demonstrated that IDH2-knockout might not exacerbate hepatic inflammatory responses in the NASH model. CONCLUSIONS: Elevated hepatic IDH2 under over-nutrition state contributes to elevated gluconeogenesis and glycogen synthesis. Inhibition of IDH2 in the liver could be a potential therapeutic target for obesity and diabetes.
Commentary on the endocrine society clinical practice guideline on the "treatment of hypercalcemia of malignancy in adults".
El-Hajj Fuleihan G, Drake MT
Metabolism · 2023 Jun · PMID 37028591 · Publisher ↗
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Corrigendum to "Genome-wide association and Mendelian randomization study of fibroblast growth factor 21 reveals causal associations with hyperlipidemia and possibly NASH" [Metab Volume 137, December 2022, 155329].
Larsson SC, Michaëlsson K, Mola-Caminal M … +2 more , Höijer J, Mantzoros CS
Metabolism · 2023 Jun · PMID 37023631 · Publisher ↗
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Monocarboxylate transporter 1 in the liver modulates high-fat diet-induced obesity and hepatic steatosis in mice.
Luo X, Li Z, Chen L … +4 more , Zhang X, Zhu X, Wang Z, Chen Y
Metabolism · 2023 Jun · PMID 36933792 · Publisher ↗
BACKGROUND: The monocarboxylate transporter 1 (MCT1) is a member of the MCT family and is implicated in the transport of lactate and a few other monocarboxylates across the cell membrane. How hepatic MCT1 regulates the m...
BACKGROUND: The monocarboxylate transporter 1 (MCT1) is a member of the MCT family and is implicated in the transport of lactate and a few other monocarboxylates across the cell membrane. How hepatic MCT1 regulates the metabolic functions of the body is currently unknown. METHODS: The functions of hepatic MCT1 on metabolism were analyzed using a mouse model with liver-specific deletion of Slc16a1 that encodes MCT1. Obesity and hepatosteatosis of the mice were induced by high-fat diet (HFD). The function of MCT1 on lactate transport was analyzed by measuring lactate level in hepatocytes and mouse liver. Degradation and polyubiquitination of PPARα protein were investigated by biochemical methods. RESULTS: Hepatic deletion of Slc16a1 aggravated high-fat diet (HFD)-induced obesity in female mice, but not in male mice. However, the increased adiposity in Slc16a1-deleted mice was not associated with obvious reductions in metabolic rate and activity. The lactate level of the liver was significantly increased by Slc16a1 deletion in the female mice under HFD condition, suggesting that MCT1 mainly mediated the efflux of lactate in hepatocytes. Deficiency of MCT1 in the liver aggravated HFD-induced hepatic steatosis in both female and male mice. Mechanistically, deletion of Slc16a1 was associated with reduced expressions of genes involved in fatty acid oxidation (FAO) in the liver. The degradation rate and polyubiquitination of PPARα protein were enhanced by Slc16a1 deletion. Blocking the MCT1 function elevated the interaction of PPARα with an E3 ubiquitin ligase HUWE1. CONCLUSIONS: Our findings suggested that the enhanced polyubiquitination and degradation of PPARα upon Slc16a1 deletion likely contributes to the reduced expression of FAO-related genes and aggravation of HFD-induced hepatic steatosis.
Epidemiology of sarcopenia: Prevalence, risk factors, and consequences.
Yuan S, Larsson SC
Metabolism · 2023 Jul · PMID 36907247 · Publisher ↗
Sarcopenia is a geriatric condition featured by a progressive loss of muscle mass and function and associated with various adverse health outcomes. In this review, we aimed to summarize the epidemiological features of sa...
Sarcopenia is a geriatric condition featured by a progressive loss of muscle mass and function and associated with various adverse health outcomes. In this review, we aimed to summarize the epidemiological features of sarcopenia as well as consequences and risk factors of the disease. We performed a systematic review of meta-analysis on sarcopenia to collect data. The prevalence of sarcopenia varied between studies and depending on definition used. Sarcopenia was estimated to influence 10 %-16 % of the elderly worldwide. The prevalence of sarcopenia was higher among patients compared to general populations. The prevalence of sarcopenia ranged from 18 % in diabetic patients to 66 % in patients with unresectable esophageal cancer. Sarcopenia is associated with a high risk of a wide range of adverse health outcomes, including poor overall and disease-progression free survival rate, postoperative complications, and longer hospitalization in patients with different medical situations as well as falls and fracture, metabolic disorders, cognitive impairment, and mortality in general populations. Physical inactivity, malnutrition, smoking, extreme sleep duration, and diabetes were associated with an increased risk of sarcopenia. However, these associations were mainly based on non-cohort observational studies and need confirmation. High-quality cohort, omics, and Mendelian randomization studies are needed to deeply understand the etiological basis of sarcopenia.
Early humoral response to COVID-19 vaccination in patients living with obesity and diabetes in France. The COVPOP OBEDIAB study with results from the ANRS0001S COV-POPART cohort.
Gaborit B, Fernandes S, Loubet P … +16 more , Ninove L, Dutour A, Cariou B, Coupaye M, Clement K, Czernichow S, Carette C, Resseguier N, Esterle L, Kali S, Houssays M, de Lamballerie X, Wittkop L, Launay O, Laville M, ANRS0001S COV-POPART study group
Metabolism · 2023 May · PMID 36731720 · Full text
BACKGROUND: Patients with diabetes and obesity are populations at high-risk for severe COVID-19 outcomes and have shown blunted immune responses when administered different vaccines. Here we used the 'ANRS0001S COV-POPAR...
BACKGROUND: Patients with diabetes and obesity are populations at high-risk for severe COVID-19 outcomes and have shown blunted immune responses when administered different vaccines. Here we used the 'ANRS0001S COV-POPART' French nationwide multicenter prospective cohort to investigate early humoral response to COVID-19 vaccination in the sub-cohort ('COVPOP OBEDIAB') of patients with obesity and diabetes. METHODS: Patients with diabetes (n = 390, type 1 or 2) or obesity (n = 357) who had received two vaccine doses and had no history of previous COVID-19 infection and negative anti-nucleocapsid (NCP) antibodies were included and compared against healthy subjects (n = 573). Humoral response was assessed at baseline, at one month post-first dose (M0) and one-month post-second dose (M1), through percentage of responders (positive anti-spike SARS-CoV-2 IgG antibodies (Sabs), geometric means of Sabs; BAU/mL), proportion of individuals with anti-RBD antibodies, and proportion of individuals with anti-SARS-CoV-2-specific neutralizing antibodies (Nabs). Potential clinical and biological factors associated with weak response (defined as Sabs < 264 BAU/mL) and presence of non-reactive anti-RBD antibodies at M1 were evaluated. Univariate and multivariate regressions were performed to estimate crude and adjusted coefficients with 95 % confidence intervals. Poor glycemic control was defined as HbA1c ≥ 7.5 % at inclusion. RESULTS: Patients with diabetes, particularly type 2 diabetes, and patients with obesity were less likely to have positive Sabs and anti-RBD antibodies after the first and second dose compared to controls (p < 0.001). At M1, we found Sabs seroconversion in 94.1 % of patients with diabetes versus 99.7 % in controls, anti-RBD seroconversion in 93.8 % of patients with diabetes versus 99.1 % in controls, and Nabs seroconversion in 95.7 % of patients with diabetes versus 99.6 % in controls (all p < 0.0001). Sabs and anti-RBD seroconversion at M0 and M1 were also significantly lower in obese patients than controls, at respectively 82.1 % versus 89.9 % (p = 0.001; M0 Sabs), 94.4 % versus 99.7 % (p 0.001; M1 Sabs), 79.0 % vs 86.2 % (p = 0.004 M0 anti-RBD), and 96.99 % vs 99.1 % (p = 0.012 M1 anti-RBD). The factors associated with low vaccine response (BAU < 264/mL) in patients with diabetes were chronic kidney disease (adjusted OR = 6.88 [1.77;26.77], p = 0.005) and poor glycemic control (adjusted OR = 3.92 [1.26;12.14], p = 0.018). In addition, BMI ≥ 40 kg/m was found to be associated with a higher vaccine response (adjusted OR = 0.10 [0.01;0.91], p = 0.040) than patients with BMI < 40 kg/m. CONCLUSION: COVID-19 vaccine humoral response was lower in patients with obesity and diabetes one month after second dose compared to controls, especially in diabetic patients with CKD or inadequate glycemic control. These findings point to the need for post-vaccination serological checks in these high-risk populations.
The global syndemic of metabolic diseases in the young adult population: A consortium of trends and projections from the Global Burden of Disease 2000-2019.
Chong B, Kong G, Shankar K … +25 more , Chew HSJ, Lin C, Goh R, Chin YH, Tan DJH, Chan KE, Lim WH, Syn N, Chan SP, Wang JW, Khoo CM, Dimitriadis GK, Wijarnpreecha K, Sanyal A, Noureddin M, Siddiqui MS, Foo R, Mehta A, Figtree GA, Hausenloy DJ, Chan MY, Ng CH, Muthiah M, Mamas MA, Chew NWS
Metabolism · 2023 Apr · PMID 36717058 · Publisher ↗
BACKGROUND: A significant proportion of premature deaths globally are related to metabolic diseases in young adults. We examined the global trends and mortality of metabolic diseases in individuals aged below 40 years us...
BACKGROUND: A significant proportion of premature deaths globally are related to metabolic diseases in young adults. We examined the global trends and mortality of metabolic diseases in individuals aged below 40 years using data from the Global Burden of Diseases, Injuries and Risk Factors Study (GBD) 2019. METHODS: From 2000 to 2019, global estimates of deaths and disability-adjusted life years (DALYs) were described for metabolic diseases (type 2 diabetes mellitus [T2DM], hyperlipidemia, hypertension, obesity, non-alcoholic fatty liver disease [NAFLD]). Subgroup analyses were performed based on sex, geographical regions and Socio-Demographic Index (SDI). Age-standardised death and DALYs were presented per 100,000 population with 95 % uncertainty intervals (UI). Projections of mortality and DALYs were estimated using regression models based on the GBD 2019 data and combining them with Institute for Health Metrics and Evaluation projection counts for years up to 2050. RESULTS: In 2019, the highest age-standardised death rates were observed in hypertension (133·88 [121·25-155·73]), followed by obesity (62·59 [39·92-89·13]), hyperlipidemia (56·51 [41·83-73·62]), T2DM (18·49 [17·18-19·66]) and NAFLD (2·09 [1·61-2·60]). Similarly, obesity (1932·54 [1276·61-2639·74]) had the highest age-standardised DALYs, followed by hypertension (2885·57 [2580·75-3201·05]), hyperlipidemia (1207·15 [975·07-1461·11]), T2DM (801·55 [670·58-954·43]) and NAFLD (53·33 [40·73-68·29]). Mortality rates decreased over time in hyperlipidemia (-0·6 %), hypertension (-0·47 %), NAFLD (-0·31 %) and T2DM (-0·20 %), but not in obesity (1·07 % increase). The highest metabolic-related mortality was observed in Eastern Mediterranean and low SDI countries. By 2050, obesity is projected to contribute to the largest number of deaths (102·8 % increase from 2019), followed by hypertension (61·4 % increase), hyperlipidemia (60·8 % increase), T2DM (158·6 % increase) and NAFLD (158·4 % increase), with males continuing to bear the greatest burden across all metabolic diseases. CONCLUSION: The growing burden of metabolic diseases, increasing obesity-related mortality trends, and the sex-regional-socioeconomic disparities evident in young adulthood, underlie the concerning growing global burden of metabolic diseases now and in future.
Females have a different metabolic response to critical illness, measured by comprehensive amino acid flux analysis.
Deutz NEP, Singer P, Wierzchowska-McNew RA … +7 more , Viana MV, Ben-David IA, Pantet O, Thaden JJ, Ten Have GAM, Engelen MPKJ, Berger MM
Metabolism · 2023 May · PMID 36717057 · Publisher ↗
BACKGROUND: The trajectory from healthy to critical illness is influenced by numerous factors, including metabolism, which differs substantially between males and females. Whole body protein breakdown is substantially in...
BACKGROUND: The trajectory from healthy to critical illness is influenced by numerous factors, including metabolism, which differs substantially between males and females. Whole body protein breakdown is substantially increased in critically ill patients, but it remains unclear whether there are sex differences that could explain the different health outcomes. Hence, we performed a secondary analysis of a study, where we used a novel pulse isotope method in critically ill and matched healthy males and females. METHODS: In 51 critically ill ICU patients (26 males, 15 females) and 49 healthy controls (36 males and 27 females), we assessed their general and disease characteristics and collected arterial(ized) blood in the postabsorptive state after pulse administration of 8 ml of a solution containing 18 stable AA tracers. In contrast to the original study, we now fitted the decay curves and calculated non-compartmental whole body amino acid production (WBP) and compartmental measurements of metabolism, including intracellular amino acid production. We measured amino acid enrichments and concentrations by LC-MS/MS and derived statistics using AN(C)OVA. RESULTS: Critically ill males and females showed an increase in the WBP of many amino acids, including those related to protein breakdown, but females showed greater elevations, or in the event of a reduction, attenuated reductions. Protein breakdown-independent WBP differences remained between males and females, notably increased glutamine and glutamate WBP. Only severely ill females showed a lower increase in WBP of many amino acids in comparison to moderately ill females, suggesting a suppressed metabolism. Compartmental analysis supported the observations. CONCLUSIONS: The present study shows that females have a different response to critical illness in the production of several amino acids and changes in protein breakdown, observations made possible using our innovative stable tracer pulse approach. CLINICAL TRIAL REGISTRY: Data are from the baseline measurements of study NCT02770092 (URL: https://clinicaltrials.gov/ct2/show/NCT02770092) and NCT03628365 (URL: https://clinicaltrials.gov/ct2/show/NCT03628365).
Adherence to the EAT-Lancet diet, genetic susceptibility, and risk of type 2 diabetes in Swedish adults.
Zhang S, Stubbendorff A, Olsson K … +5 more , Ericson U, Niu K, Qi L, Borné Y, Sonestedt E
Metabolism · 2023 Apr · PMID 36682448 · Publisher ↗
BACKGROUND AND AIMS: In 2019, the EAT-Lancet Commission proposed a mainly plant-based diet that nurtures human health and supports environmental sustainability. However, its association with type 2 diabetes (T2D) has not...
BACKGROUND AND AIMS: In 2019, the EAT-Lancet Commission proposed a mainly plant-based diet that nurtures human health and supports environmental sustainability. However, its association with type 2 diabetes (T2D) has not been widely studied, and it remains unclear whether genetic susceptibility for T2D can modify this association. The aim was therefore to investigate the association between the EAT-Lancet diet and risk of T2D and assess whether the association differs by the genetic predisposition to T2D. METHODS: A total of 24,494 participants from the Malmö Diet and Cancer study were analyzed. Dietary intake was assessed using a modified diet history methodology, and an EAT-Lancet diet index (range from 0 to 42 points) was constructed based on the EAT-Lancet reference diet. National and local registers were used to identify T2D cases during follow-up. Cox proportional hazards regression model was applied to estimate the association between the EAT-Lancet diet index and risk of T2D. Genetic predisposition to T2D was captured based on 116 single nucleotide polymorphisms. RESULTS: During a median of 24.3 years of follow-up, 4197 (17.1 %) T2D cases were documented. Compared with those with the lowest adherence to the EAT-Lancet diet (≤13 points), participants who had the highest adherence (≥23 points) showed an 18 % (95 % CI: 4 %-30 %) lower risk of T2D (P for trend <0.01). There was no significant multiplicative interaction between genetic predisposition to T2D and the EAT-Lancet diet index (P = 0.59). Also, no significant additive interaction between the genetic risk and the EAT-Lancet diet was seen (P = 0.44). The highest risk was observed among the 22.9 % of the individuals with high genetic risk and low EAT-Lancet diet score (HR = 1.79; 95 % CI: 1.63, 1.96). CONCLUSIONS: Our findings indicate that high adherence to the EAT-Lancet diet was associated with decreased risk of incident T2D among people with different genetic risks.
Effects of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on substrate metabolism in prediabetic insulin resistant individuals: A randomized, double-blind crossover trial.
Veelen A, Andriessen C, Op den Kamp Y … +12 more , Erazo-Tapia E, de Ligt M, Mevenkamp J, Jörgensen JA, Moonen-Kornips E, Schaart G, Esterline R, Havekes B, Oscarsson J, Schrauwen-Hinderling VB, Phielix E, Schrauwen P
Metabolism · 2023 Mar · PMID 36592688 · Publisher ↗
AIMS/HYPOTHESIS: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment in type 2 diabetes mellitus patients results in glucosuria, causing an energy loss, and triggers beneficial metabolic adaptations. It is so far...
AIMS/HYPOTHESIS: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment in type 2 diabetes mellitus patients results in glucosuria, causing an energy loss, and triggers beneficial metabolic adaptations. It is so far unknown if SGLT2i exerts beneficial metabolic effects in prediabetic insulin resistant individuals, yet this is of interest since SGLT2is also reduce the risk for progression of heart failure and chronic kidney disease in patients without diabetes. METHODS: Fourteen prediabetic insulin resistant individuals (BMI: 30.3 ± 2.1 kg/m; age: 66.3 ± 6.2 years) underwent 2-weeks of treatment with dapagliflozin (10 mg/day) or placebo in a randomized, placebo-controlled, cross-over design. Outcome parameters include 24-hour and nocturnal substrate oxidation, and twenty-four-hour blood substrate and insulin levels. Hepatic glycogen and lipid content/composition were measured by MRS. Muscle biopsies were taken to measure mitochondrial oxidative capacity and glycogen and lipid content. RESULTS: Dapagliflozin treatment resulted in a urinary glucose excretion of 36 g/24-h, leading to a negative energy and fat balance. Dapagliflozin treatment resulted in a higher 24-hour and nocturnal fat oxidation (p = 0.043 and p = 0.039, respectively), and a lower 24-hour carbohydrate oxidation (p = 0.048). Twenty-four-hour plasma glucose levels were lower (AUC; p = 0.016), while 24-hour free fatty acids and nocturnal β-hydroxybutyrate levels were higher (AUC; p = 0.002 and p = 0.012, respectively) after dapagliflozin compared to placebo. Maximal mitochondrial oxidative capacity was higher after dapagliflozin treatment (dapagliflozin: 87.6 ± 5.4, placebo: 78.1 ± 5.5 pmol/mg/s, p = 0.007). Hepatic glycogen and lipid content were not significantly changed by dapagliflozin compared to placebo. However, muscle glycogen levels were numerically higher in the afternoon in individuals on placebo (morning: 332.9 ± 27.9, afternoon: 368.8 ± 13.1 nmol/mg), while numerically lower in the afternoon on dapagliflozin treatment (morning: 371.7 ± 22.8, afternoon: 340.5 ± 24.3 nmol/mg). CONCLUSIONS/INTERPRETATION: Dapagliflozin treatment of prediabetic insulin resistant individuals for 14 days resulted in significant metabolic adaptations in whole-body and skeletal muscle substrate metabolism despite being weight neutral. Dapagliflozin improved fat oxidation and ex vivo skeletal muscle mitochondrial oxidative capacity, mimicking the effects of calorie restriction. TRIAL REGISTRATION: ClinicalTrials.gov NCT03721874.
Activins, follistatins and inhibins in postmenopausal osteoporosis: A proof of concept, case-control study.
Anastasilakis AD, Polyzos SA, Rodopaios NE … +4 more , Makras P, Kumar A, Kalra B, Mantzoros CS
Metabolism · 2023 Apr · PMID 36587801 · Publisher ↗
BACKGROUND: Bone metabolism has been proposed to be affected by the activins-follistatins-inhibins (AFI) hormonal system. We aimed to evaluate AFI in patients with osteoporosis and osteopenia compared with postmenopausal...
BACKGROUND: Bone metabolism has been proposed to be affected by the activins-follistatins-inhibins (AFI) hormonal system. We aimed to evaluate AFI in patients with osteoporosis and osteopenia compared with postmenopausal and premenopausal controls. METHODS: In this case-control study, circulating levels of the AFI system were evaluated, individually and jointly, between postmenopausal women with osteoporosis (BMD T-score ≤-2.5; n = 25) or osteopenia (BMD T-score >-2.5 and ≤-1; n = 25) and postmenopausal women with normal BMD (T-score >-1.0; n = 25) or premenopausal women with normal BMD (Z-score >-1.0; n = 25), with and without adjustment for potential confounders. RESULTS: In the sum of participants, AFI molecules and their ratios followed an opposite pattern of correlations for age and BMI vs. BMD. In unadjusted models, FSTL3 concentrations were higher, whereas activin B, inhibin A and inhibin B and the ratios of activin B/follistatin and activin B/FSTL3 were lower in the three postmenopausal groups compared with the premenopausal group. Activin A/follistatin and activin AB/follistatin ratios were lower in the osteoporosis group than the other three groups. After adjustment for BMI and age, inhibin B (p = 0.005), and the ratios of activin A/follistatin (p = 0.009), activin B/follistatin (p = 0.040) and activin AB/follistatin (p = 0.003) were lower in the osteoporotic group compared with the other groups. In fully adjusted logistic regression analysis log(inhibin B) (p = 0.041), log(activinA/follistatin) (p = 0.014), log(activinB/follistatin) (p = 0.025) and log(activinAB/follistatin) (p = 0.021), but not FSTL3, remained independently associated with the presence of osteoporosis. CONCLUSIONS: Lower inhibin B and higher ratios of activins A, B, and AB to follistatin are associated with lumbar spine BMD and the presence of osteoporosis independently from age or BMI.
Adipose tissue adipokines and lipokines: Functions and regulatory mechanism in skeletal muscle development and homeostasis.
Gu X, Wang L, Liu S … +1 more , Shan T
Metabolism · 2023 Feb · PMID 36538987 · Publisher ↗
Skeletal muscle plays important roles in normal biological activities and whole-body energy homeostasis in humans. The growth and development of skeletal muscle also directly influence meat production and meat quality in...
Skeletal muscle plays important roles in normal biological activities and whole-body energy homeostasis in humans. The growth and development of skeletal muscle also directly influence meat production and meat quality in animal production. Therefore, regulating the development and homeostasis of skeletal muscle is crucial for human health and animal production. Adipose tissue, which includes white adipose tissue (WAT) and brown adipose tissue (BAT), not only functions as an energy reserve but also has attracted substantial attention because of its role as an endocrine organ. The novel signalling molecules known as "adipokines" and "lipokines" that are secreted by adipose tissue were identified through the secretomic technique, which broadened our understanding of the previously unknown crosstalk between adipose tissue and skeletal muscle. In this review, we summarize and discuss the secretory role of adipose tissues, both WAT and BAT, as well as the regulatory roles of various adipokines and lipokines in skeletal muscle development and homeostasis. We suggest that adipokines and lipokines have potential as drug candidates for the treatment of skeletal muscle dysfunction and related metabolic diseases and as promising nutrients for improving animal production.
Glucagon-like peptide-1 secretion in people with versus without type 2 diabetes: a systematic review and meta-analysis of cross-sectional studies.
Watkins JD, Carter S, Atkinson G … +4 more , Koumanov F, Betts JA, Holst JJ, Gonzalez JT
Metabolism · 2023 Mar · PMID 36502882 · Publisher ↗
AIMS/HYPOTHESIS: The aim of this systematic review was to synthesise the study findings on whether GLP-1 secretion in response to a meal tolerance test is affected by the presence of type 2 diabetes (T2D). The influence...
AIMS/HYPOTHESIS: The aim of this systematic review was to synthesise the study findings on whether GLP-1 secretion in response to a meal tolerance test is affected by the presence of type 2 diabetes (T2D). The influence of putative moderators such as age, sex, meal type, meal form, and assay type were also explored. METHODS: A literature search identified 32 relevant studies. The sample mean and SD for fasting GLP-1 and GLP-1 iAUC were extracted and used to calculate between-group standardised mean differences (SMD), which were meta-analysed using a random-effects model to derive pooled estimates of Hedges' g and 95 % prediction intervals (PI). RESULTS: Pooled across 18 studies, the overall SMD in GLP-1 iAUC between individuals with T2D (n = 270, 1047 ± 930 pmol·L·min) and individuals without T2D (n = 402, 1204 ± 937 pmol·L·min) was very small, not statistically significant and heterogenous across studies (g = -0.15, p = 0.43, PI: -1.53, 1.23). Subgroup analyses demonstrated an effect of assay type whereby Hedges' g for GLP-1 iAUC was greater in individuals with, versus those without T2D when using ELISA or Mesoscale (g = 0.67 [moderate], p = 0.009), but not when using RIA (g = -0.30 [small], p = 0.10). Pooled across 30 studies, the SMD in fasting GLP-1 between individuals with T2D (n = 580, 16.2 ± 6.9 pmol·L) versus individuals without T2D (n = 1363, 12.4 ± 5.7 pmol·L) was small and heterogenous between studies (g = 0.24, p = 0.21, PI: -1.55, 2.02). CONCLUSIONS: Differences in fasting GLP-1 and GLP-1 iAUC between individuals with, versus those without T2D were generally small and inconsistent between studies. Factors influencing study heterogeneity such as small sample sizes and poor matching of groups may help to explain the wide prediction intervals observed. Considerations to improve comparisons of GLP-1 secretion in T2D and potential mediating factors more important than T2D diagnosis per se are outlined. PROSPERO ID: CRD42020195612.
SUMOylation of ERp44 enhances Ero1α ER retention contributing to the pathogenesis of obesity and insulin resistance.
Xie H, Wang YH, Liu X … +17 more , Gao J, Yang C, Huang T, Zhang L, Luo X, Gao Z, Wang T, Yan T, Liu Y, Yang P, Yu Q, Liu S, Wang Y, Xiong F, Zhang S, Zhou Q, Wang CY
Metabolism · 2023 Feb · PMID 36427672 · Publisher ↗
OBJECTIVE: As the only E2 conjugating enzyme for the SUMO system, Ubc9-mediated SUMOylation has been recognized to regulate diverse biological processes, but its impact on adipocytes relevant to obesity and insulin resis...
OBJECTIVE: As the only E2 conjugating enzyme for the SUMO system, Ubc9-mediated SUMOylation has been recognized to regulate diverse biological processes, but its impact on adipocytes relevant to obesity and insulin resistance is yet to be elucidated. METHODS: We established adipocyte-specific Ubc9 deficient mice to explore the effects of Ubc9 on obesity and metabolic disorders induced by high-fat diet (HFD) in adult mice. The molecular targets of SUMOylation were explored by liquid chromatography-mass spectrometry, and the regulatory mechanism of SUMOylation in T2D was analyzed. RESULTS: Adipocyte-specific depletion of Ubc9 (AdipoQ-Cre-Ubc9, Ubc9) protected mice from HFD-induced obesity, insulin resistance, and hepatosteatosis. The Ubc9 mice were featured by the reduced HFD-induced endoplasmic reticulum (ER) stress and inflammatory response. Mechanically, over nutrition rendered adipocytes to undergo a SUMOylation turnover characterized by the change of SUMOylation levels and substrates. ERp44 displayed the highest change in terms of SUMOylation levels of substrates involved in ER-related functions. The lack of ERp44 SUMOylation at lysine 76 (K76) located within the thioredoxin (TRX)-like domain by Ubc9 deficiency enhanced its degradation and suppressed its covalent binding to Ero1α, an oxidase that exists in the ER but lacks ER retention motif, thereby alleviating endoplasmic reticulum stress by promoting Ero1α secretion. CONCLUSIONS: Our data suggest that modulation of ERp44 SUMOylation in adipocytes could be a feasible strategy against obesity and insulin resistance in clinical settings.
Circulating lipoprotein(a) levels and health outcomes: Phenome-wide Mendelian randomization and disease-trajectory analyses.
Larsson SC, Wang L, Li X … +3 more , Jiang F, Chen X, Mantzoros CS
Metabolism · 2022 Dec · PMID 36396079 · Publisher ↗
BACKGROUND: Lipoprotein(a) [Lp(a)] is a risk factor for atherosclerotic and valvular diseases, but its possible role in other diseases has not yet been established. We conducted phenome-wide Mendelian randomization and d...
BACKGROUND: Lipoprotein(a) [Lp(a)] is a risk factor for atherosclerotic and valvular diseases, but its possible role in other diseases has not yet been established. We conducted phenome-wide Mendelian randomization and disease-trajectory analyses to assess any associations of circulating Lp(a) levels with a broad range of diseases. METHODS: A weighted polygenic risk score was constructed using independent genetic variants in the LPA gene and with an established effect on Lp(a) levels. The PheWAS analysis included 1081 phenotype outcomes ascertained among 385,917 White participants of the UK Biobank. Novel findings were investigated in MR analysis using data from the FinnGen consortium. Disease-trajectory and comorbidity analyses were further conducted to explore the sequential patterns of multiple morbidities related to high circulating Lp(a) levels. RESULTS: PheWAS revealed statistically significant associations of higher circulating Lp(a) levels with increased risk of a large number of circulatory system diseases (including various cardiac diseases, peripheral vascular disease, hypertension, and valvular and cerebrovascular diseases) as well as some endocrine/metabolic diseases (including hyperlipidemia, hypercholesterolemia, disorders of lipoid metabolism, and type 2 diabetes), genitourinary system diseases (renal failure), and hematologic diseases (including different types of anemia). Two-sample MR analysis supported the association between Lp(a) and risk of anemia, showed a suggestive association with type 2 diabetes, but found no association with renal failure. Disease-trajectory and comorbidity analyses identified 3 major sequential patterns of multiple morbidities, mainly in the cardiovascular, metabolic, and mental disorders, related to high circulating Lp(a) levels. CONCLUSIONS: Genetically predicted higher circulating Lp(a) levels were associated with increased risk of many circulatory system diseases and anemia. Additionally, this study identified three major sequential patterns of multiple morbidities related to high Lp(a).
Early metabolomic, lipid and lipoprotein changes in response to medical and surgical therapeutic approaches to obesity.
Angelidi AM, Kokkinos A, Sanoudou D … +4 more , Connelly MA, Alexandrou A, Mingrone G, Mantzoros CS
Metabolism · 2023 Jan · PMID 36375643 · Publisher ↗
BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and bariatric surgery have proven to be effective treatments for obesity and cardiometabolic conditions. We aimed to explore the early metabolomic changes i...
BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and bariatric surgery have proven to be effective treatments for obesity and cardiometabolic conditions. We aimed to explore the early metabolomic changes in response to GLP-1RA (liraglutide) therapy vs. placebo and in comparison to bariatric surgery. METHODS: Three clinical studies were conducted: a bariatric surgery cohort study of participants with morbid obesity who underwent either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) studied over four and twelve weeks, and two randomized placebo-controlled, crossover double blind studies of liraglutide vs. placebo administration in participants with type 2 diabetes (T2D) and participants with obesity studied for three and five weeks, respectively. Nuclear magnetic resonance spectroscopy-derived metabolomic data were assessed in all eligible participants who completed all the scheduled in-clinic visits. The primary outcome of the study was to explore the changes of the metabolome among participants with obesity with and without T2D receiving the GLP-1RA liraglutide vs. placebo and participants with obesity undergoing bariatric surgery during the three to five-week study period. In addition, we assessed the bariatric surgery effects longitudinally over the twelve weeks of the study and the differences between the bariatric surgery subgroups on the metabolome. The trials are registered with ClinicalTrials.gov, numbers NCT03851874, NCT01562678 and NCT02944500. RESULTS: Bariatric surgery had a more pronounced effect on weight and body mass index reduction (-14.19 ± 5.27 kg and - 5.19 ± 5.27, respectively, p < 0.001 for both) and resulted in more pronounced metabolomic and lipidomic changes compared to liraglutide therapy at four weeks postoperatively. Significant changes were observed in lipoprotein parameters, inflammatory markers, ketone bodies, citrate, and branched-chain amino acids after the first three to five weeks of intervention. After adjusting for the amount of weight loss, a significant difference among the study groups remained only for acetoacetate, β-hydroxybutyrate, and citrate (p < 0.05 after FDR correction). Glucose levels were significantly reduced in all intervention groups but mainly in the T2D group receiving GLP-1RA treatment. After adjusting for weight loss, only glucose levels remained significant (p = 0.001 after FDR correction), mainly due to the glucose change in the T2D group receiving GLP-1RA. Similar results with those observed at four weeks were observed in the surgical group when delta changes at twelve weeks were assessed. Comparing the two types of bariatric surgery, an intervention effect was more pronounced in the RYGB subgroup regarding total triglycerides, triglyceride-rich lipoprotein size, and trimethylamine-N-oxide (p for intervention: 0.031, 0.028, 0.036, respectively). However, after applying FDR correction, these changes deemed to be only suggestive; only time effects remained significant with no significant changes persisting in relation to the types of bariatric surgery. CONCLUSIONS: The results of this study suggest that the early metabolomic, lipid and lipoprotein changes observed between liraglutide treatment and bariatric surgery are similar and result largely from the changes in patients' body weight. Specific changes observed in the short-term post-surgical period between bariatric vs. nonsurgical treated participants, i.e., acetoacetate, β-hydroxybutyrate, and citrate changes, may reflect changes in patient diets and calorie intake indicating potential calorie and diet-driven metabolomics/lipidomic effects in the short-term postoperatively. Significant differences observed between SG and RYGB need to be confirmed and extended by future studies.
Loss of long-chain acyl-CoA synthetase 1 promotes hepatocyte death in alcohol-induced steatohepatitis.
Dong H, Zhong W, Zhang W … +7 more , Hao L, Guo W, Yue R, Sun X, Sun Z, Bataller R, Zhou Z
Metabolism · 2023 Jan · PMID 36349655 · Full text
BACKGROUND: Alcohol consumption has been shown to disrupt hepatic lipid homeostasis. Long-chain acyl-CoA synthetase 1 (ACSL1) critically regulates hepatic fatty acid metabolism and lipid homeostasis by channeling fatty a...
BACKGROUND: Alcohol consumption has been shown to disrupt hepatic lipid homeostasis. Long-chain acyl-CoA synthetase 1 (ACSL1) critically regulates hepatic fatty acid metabolism and lipid homeostasis by channeling fatty acids to lipid metabolic pathways. However, it remains unclear how ACSL1 contributes to the development of alcohol-associated liver disease (ALD). METHODS: We performed chronic alcohol feeding animal studies with hepatocyte-specific ACSL1 knockout (ACSL1) mice, hepatocyte-specific STAT5 knockout (STAT5) mice, and ACSL1 based-STAT5B overexpression (Stat5b-OE) mice. Cell studies were conducted to define the causal role of ACSL1 deficiency in the pathogenesis of alcohol-induced liver injury. The clinical relevance of the STAT5-ACSL1 pathway was examined using liver tissues from patients with alcoholic hepatitis (AH) and normal subjects (Normal). RESULTS: We found that chronic alcohol consumption reduced hepatic ACSL1 expression in AH patients and ALD mice. Hepatocyte-specific ACSL1 deletion exacerbated alcohol-induced liver injury by increasing free fatty acids (FFA) accumulation and cell death. Cell studies revealed that FFA elicited the translocation of BAX and p-MLKL to the lysosomal membrane, resulting in lysosomal membrane permeabilization (LMP) and thereby initiating lysosomal-mediated cell death pathway. Furthermore, we identified that the signal transducer and activator of transcription 5 (STAT5) is a novel transcriptional regulator of ACSL1. Deletion of STAT5 exacerbated alcohol-induced liver injury in association with downregulation of ACSL1, and reactivation of ACSL1 by STAT5 overexpression effectively ameliorated alcohol-induced liver injury. In addition, ACSL1 expression was positively correlated with STAT5 and negatively correlated with cell death was also validated in the liver of AH patients. CONCLUSIONS: ACSL1 deficiency due to STAT5 inactivation critically mediates alcohol-induced lipotoxicity and cell death in the development of ALD. These findings provide insights into alcohol-induced liver injury.
Metabolism, Clinical and Experimental: seventy years young and growing.
Polyzos SA, Hill MA, Fuleihan GE … +8 more , Gnudi L, Kim YB, Larsson SC, Masuzaki H, Matarese G, Sanoudou D, Tena-Sempere M, Mantzoros CS
Metabolism · 2022 Dec · PMID 36244415 · Publisher ↗
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Pharmacotherapy of type 2 diabetes: An update and future directions.
DeMarsilis A, Reddy N, Boutari C … +4 more , Filippaios A, Sternthal E, Katsiki N, Mantzoros C
Metabolism · 2022 Dec · PMID 36240884 · Publisher ↗
Type 2 diabetes (T2D) is a widely prevalent disease with substantial economic and social impact for which multiple conventional and novel pharmacotherapies are currently available; however, the landscape of T2D treatment...
Type 2 diabetes (T2D) is a widely prevalent disease with substantial economic and social impact for which multiple conventional and novel pharmacotherapies are currently available; however, the landscape of T2D treatment is constantly changing as new therapies emerge and the understanding of currently available agents deepens. This review aims to provide an updated summary of the pharmacotherapeutic approach to T2D. Each class of agents is presented by mechanism of action, details of administration, side effect profile, cost, and use in certain populations including heart failure, non-alcoholic fatty liver disease, obesity, chronic kidney disease, and older individuals. We also review targets of novel therapeutic T2D agent development. Finally, we outline an up-to-date treatment approach that starts with identification of an individualized goal for glycemic control then selection, initiation, and further intensification of a personalized therapeutic plan for T2D.
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