Mice with Whole-Body Disruption of AMPK-Glycogen Binding Have Increased Adiposity, Reduced Fat Oxidation and Altered Tissue Glycogen Dynamics.
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ABSTRACT:
SUBMITTER: Janzen NR
PROVIDER: S-EPMC8431764 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We investigated the effects of endurance training on the expression of long-chain fatty acid transport proteins in the skeletal muscle and whole-body fat oxidation during endurance exercise.Seven-week-old male ICR mice (n = 12) were divided into 2 groups, namely, Sed (sedentary; non-trained) and Tr (endurance-trained) groups. The Tr group was adapted to treadmill training at a fixed intensity (15 m/min, 8° slope) for 3 days. Next, the exercise intensity was increased while maintaining the 8° slope. In the last week of training, the exercise intensity was set at 25 m/min for 50 min (about 70-75% maximal oxygen uptake for 4 weeks). After the protocol ended, the mice were sacrificed, and tissues were collected for western blot analysis.Four weeks of endurance training resulted in a significant increase in the protein levels of FAT/CD36 and CPTІ. The FAT/ CD36 protein level in the Tr group was about 1.3-fold greater than that in the Sed group (p < 0.01). Furthermore, the increased CPTІ indicated higher activity (19% upregulation) in the Tr group compared to the Sed group (p < 0.05). The FAT/CD36 protein level and the estimated whole-body fat oxidation rate during 1-h exercise were found to be significantly correlated (r = 0.765, p < 0.01).We suggest that the increase in FAT/CD36 protein in skeletal muscle by endurance training might be positively associated with whole-body fat oxidation, which might enhance endurance exercise capacity.
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Project description:This study had two main objectives: To examine the association between body fat distribution and non-alcoholic fatty liver disease (NAFLD) and liver fat content, and to determine whether the relationship between NAFLD and regional body fat distribution, with respect to liver fat content in youths with excess adiposity, is independent of cardiorespiratory fitness (CRF) and a healthy diet. Liver fat content (controlled attenuation parameter (CAP)), body fat distribution (body mass index (BMI) z-score, waist circumference, waist-to-height ratio, fat mass/height, body fat percentage, total fat mass, android-to-gynoid fat mass ratio, visceral adipose tissue (VAT), and lean mass index, determined by dual-energy X-ray absorptiometry (DXA)), CRF (20-m shuttle-run test), and healthy diet (adherence to the Mediterranean diet by KIDMED questionnaire) were measured in 126 adolescents (66% girls) aged between 11 and 17 years. Participants were assigned to two groups according to the presence or absence of hepatic steatosis (CAP values ?225 dB/m or <225 dB/m of liver fat, respectively). Considering the similar total fat values for the two groups (>30% by DXA), youths with NAFLD had higher fat distribution parameters than those without NAFLD, regardless of sex, age, puberty stage, lean mass index, CRF, and healthy diet (p < 0.01). In the non-NAFLD group, the association between hepatic fat and fat distribution parameters presented a similar pattern, although the association was statistically insignificant after adjusting for a potential confounding variable (ps > 0.05), except for the case of VAT. Body fat distribution parameters were higher in youths with NAFLD compared to those without NAFLD. Additionally, body fat distribution showed a significant association with liver fat content as assessed by CAP in youths with NAFLD independent of CRF and adherence to the Mediterranean diet, supporting the notion that upper body fat distribution might play a pivotal role in the development of NAFLD in adolescents. These results may have implications for the clinical management of youths with excess adiposity given the high prevalence of NAFLD in children and young adults.
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Project description:Activation of AMP-activated protein kinase (AMPK) is thought to convey many of the beneficial effects of exercise via its inhibitory effect on acetyl-CoA carboxylase 2 (ACC2) and promotion of fatty acid oxidation. Hence, AMPK and ACC have become major drug targets for weight loss and improved insulin action. However, it remains unclear whether or how activation of the fatty acid oxidation pathway without a concomitant increase in energy expenditure could be beneficial. Here, we have used either pharmacological (administration of the AMPK agonist 5(') aminoimidazole-4-carboxamide-riboside) or genetic means (mutation of the ACC2 gene in mice) to manipulate fatty acid oxidation to determine whether this is sufficient to promote leanness. Both of these strategies increased whole-body fatty acid oxidation without altering energy expenditure or adiposity. We conclude that negative energy balance is a prerequisite for weight reduction, and increased fatty acid oxidation per se has little, if any, effect to reduce adiposity.
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Project description:Brain insulin action regulates eating behavior and energy fluxes throughout the body. However, numerous people are brain insulin resistant. How brain insulin responsiveness affects long-term weight and body fat composition in humans is still unknown. Here we show that high brain insulin sensitivity before lifestyle intervention associates with a more pronounced reduction in total and visceral fat during the program. High brain insulin sensitivity is also associated with less regain of fat mass during a nine year follow-up. Cross-sectionally, strong insulin responsiveness of the hypothalamus associates with less visceral fat, while subcutaneous fat is unrelated. Our results demonstrate that high brain insulin sensitivity is linked to weight loss during lifestyle intervention and associates with a favorable body fat distribution. Since visceral fat is strongly linked to diabetes, cardiovascular risk and cancer, these findings have implications beyond metabolic diseases and indicate the necessity of strategies to resolve brain insulin resistance.
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Project description:Myosteatosis is the pathologic accumulation of lipid that can occur in conjunction with atrophy and fibrosis following skeletal muscle injury. Little is known about the mechanisms by which lipid accumulates in myosteatosis, but many clinical studies have demonstrated that the degree of lipid infiltration negatively correlates with muscle function and regeneration. Our objective was to determine the pathologic changes that result in lipid accumulation in injured muscle fibers. We used a rat model of rotator cuff injury in this study because the rotator cuff muscle group is particularly prone to the development of myosteatosis after injury. Muscles were collected from uninjured controls or 10, 30, or 60 d after injury and analyzed using a combination of muscle fiber contractility assessments, RNA sequencing, and undirected metabolomics, lipidomics, and proteomics, along with bioinformatics techniques to identify potential pathways and cellular processes that are dysregulated after rotator cuff tear. Bioinformatics analyses indicated that mitochondrial function was likely disrupted after injury. Based on these findings and given the role that mitochondria play in lipid metabolism, we then performed targeted biochemical and imaging studies and determined that mitochondrial dysfunction and reduced fatty acid oxidation likely leads to the accumulation of lipid in myosteatosis.-Gumucio, J. P., Qasawa, A. H., Ferrara, P. J., Malik, A. N., Funai, K., McDonagh, B., Mendias, C. L. Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis.
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Project description:Obesity is a well-known risk factor for the development and progression of chronic kidney disease. Recently, para-perirenal ultrasonographic fat thickness (PUFT) has shown to correlate with both total and visceral fat better than body mass index (BMI), waist circumference (WC), and other indices of obesity. Moreover, a local paracrine and mechanical action of the PUFT on kidney has been described in recent studies. Aim of our study was to assess the relationship between glomerular filtration rate (GFR) and PUFT in comparison with other anthropometric and ultrasonographic indices of adiposity. Two hundred and ninety-six hypertensive patients were enrolled. PUFT, cutis-rectis thickness and rectis-aorta thickness were obtained by ultrasonography. Anthropometric measures of adiposity were also measured. Estimated GFR was calculated using the CKD-EPI equation. Higher PUFT values were observed in patients with impaired renal function (P < 0.001), whereas no differences in BMI and WC were shown between groups divided by GFR. PUFT significantly correlated with GFR in all patients (r = -0.284; P < 0.001), with no differences in groups divided by sex, diabetes, or BMI. This association held in multivariate analyses also after correction for confounding factors, including other adiposity indices (P < 0.001). When receiver operating characteristic curves were built to detect a eGFR < 60 mL/minutes per 1.73 m2 , a PUFT value ≤3.725 cm showed a negative predictive value of 94.0%, with the largest area under the curve (AUC: 0.700) among the variables considered. In conclusion, the relationship between PUFT and GFR seems to be more accurate and less influenced by the bias affecting traditional indices of adiposity.
| S-EPMC8030936 | biostudies-literature
Project description:Male patients with Peutz-Jeghers syndrome (PJS) have defective spermatogenesis and are at increased risk of developing Sertoli cell tumors. Mutations in the Liver Kinase B1 (LKB1/STK11) gene are associated with the pathogenesis of PJS and have been identified in non-PJS patients with sporadic testicular cancers. The mechanisms controlled by LKB1 signaling in Sertoli cell functions and testicular biology have not been described. We have conditionally deleted the Lkb1 gene (Lkb1(cko)) in somatic testicular cells to define the molecular mechanisms involved in the development of the testicular phenotype observed in PJS patients. Focal vacuolization in some of the seminiferous tubules was observed in 4-week-old mutant testes but germ cell development appeared to be normal. However, similar to PJS patients, we observed progressive germ cell loss and Sertoli cell only tubules in Lkb1(cko) testes from mice older than 10 weeks, accompanied by defects in Sertoli cell polarity and testicular junctional complexes and decreased activation of the MAP/microtubule affinity regulating and focal adhesion kinases. Suppression of AMP kinase and activation of mammalian target of rapamycin (mTOR) signaling were also observed in Lkb1(cko) testes. Loss of Tsc1 or Tsc2 copies the progressive Lkb1(cko) phenotype, suggesting that dysregulated activation of mTOR contributes to the pathogenesis of the Lkb1(cko) testicular phenotype. Pten(cko) mice had a normal testicular phenotype, which could be explained by the comparative lack of mTOR activation detected. These studies describe the importance of LKB1 signaling in testicular biology and the possible molecular mechanisms driving the pathogenesis of the testicular defects observed in PJS patients.
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Project description:The body adiposity index (BAI) estimates the amount of body fat (BF) in humans. In Mexican-American and African-American populations, BAI has performed better than body mass index (BMI). The aim of this study was to evaluate the performance of BAI in estimating percentage (BF%) in severely obese Brazilian patients, with air displacement plethysmography (ADP) used as the reference method.Estimation of BF% by ADP, anthropometric measurements (height, abdominal and hip circumferences, body weight, and BMI) and BAI calculation were performed in 72 obese subjects (BMI ? 30 kg/m(2)) aged 30-55 years.The mean BF% estimates ± standard deviation were 52.1 ± 5.7 % for ADP and 47.7 ± 7.4% for BAI, with a positive Pearson correlation (rp = 0.66) and a positive Lin's concordance correlation (rc = 0.479) observed between these methods. The 95% limits of individual agreement between BAI and ADP ranged from -5.769% to 16.036%, with BAI exhibiting an average positive bias of 5.13% compared to the reference method. For each studied variable, BAI exhibited a systematic bias, as evidenced by a tendency for low BF% values to be overestimated.For Brazilian patients with severe obesity, BAI does not provide an accurate estimate of BF%.
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Project description:Organisms must utilize multiple mechanisms to maintain energetic homeostasis in the face of limited nutrient availability. One mechanism involves activation of the heterotrimeric AMP-activated protein kinase (AMPK), a cell-autonomous sensor to energetic changes regulated by ATP to AMP ratios. We examined the phenotypic consequences of reduced AMPK function, both through RNAi knockdown of the gamma subunit (AMPK?) and through expression of a dominant negative alpha (AMPK?) variant in Drosophila melanogaster. Reduced AMPK signaling leads to hypersensitivity to starvation conditions as measured by lifespan and locomotor activity. Locomotor levels in flies with reduced AMPK function were lower during unstressed conditions, but starvation-induced hyperactivity, an adaptive response to encourage foraging, was significantly higher than in wild type. Unexpectedly, total dietary intake was greater in animals with reduced AMPK function yet total triglyceride levels were lower. AMPK mutant animals displayed starvation-like lipid accumulation patterns in metabolically key liver-like cells, oenocytes, even under fed conditions, consistent with a persistent starved state. Measurements of O(2) consumption reveal that metabolic rates are greater in animals with reduced AMPK function. Lastly, rapamycin treatment tempers the starvation sensitivity and lethality associated with reduced AMPK function. Collectively, these results are consistent with models that AMPK shifts energy usage away from expenditures into a conservation mode during nutrient-limited conditions at a cellular level. The highly conserved AMPK subunits throughout the Metazoa, suggest such findings may provide significant insight for pharmaceutical strategies to manipulate AMPK function in humans.
| S-EPMC2942814 | biostudies-literature
Project description:BackgroundVitamin D status of pregnant women is associated with body composition of the offspring. The objective of this study was to assess whether the association between maternal vitamin D status and neonatal adiposity is modified by maternal adiposity preconception.MethodsHealthy mothers and their term appropriate weight for gestational age (AGA) infants (n = 142; 59% male, Greater Montreal, March 2016-2019) were studied at birth and 1 month postpartum (2-6 weeks). Newborn (24-36 h) serum was collected to measure total 25-hydroxyvitamin D [25(OH)D] (immunoassay); maternal pre-pregnancy BMI was obtained from the medical record. Anthropometry, body composition (dual-energy X-ray absorptiometry) and serum 25(OH)D were measured at 2-6 weeks postpartum in mothers and infants. Mothers were grouped into 4 categories based on their vitamin D status (sufficient 25(OH)D ≥ 50 nmol/L vs. at risk of being insufficient < 50 nmol/L) and pre-pregnancy BMI (< 25 vs. ≥25 kg/m2): insufficient-recommended weight (I-RW, n = 24); insufficient-overweight/obese (I-OW/O, n = 21); sufficient-recommended weight (S-RW, n = 69); and sufficient-overweight/obese (S-OW/O, n = 28). Partial correlation and linear fixed effects model were used while adjusting for covariates.ResultsAt birth, infant serum 25(OH)D mean concentrations were below 50 nmol/L, the cut-point for sufficiency, for both maternal pre-pregnancy BMI categories; 47.8 [95%CI: 43.8, 51.9] nmol/L if BMI < 25 kg/m2 and 38.1 [95%CI: 33.5, 42.7] nmol/L if BMI ≥25 kg/m2. Infant serum 25(OH)D concentrations at birth (r = 0.77; P < 0.0001) and 1 month (r = 0.59, P < 0.0001) were positively correlated with maternal postpartum serum 25(OH)D concentrations. Maternal serum 25(OH)D concentration was weakly correlated with maternal percent whole body fat mass (r = - 0.26, P = 0.002). Infants of mothers in I-OW/O had higher fat mass versus those of mothers in S-OW/O (914.0 [95%CI: 766.4, 1061.6] vs. 780.7 [95%CI: 659.3, 902.0] g; effect size [Hedges' g: 0.42]; P = 0.04 adjusting for covariates) with magnitude of difference of 220.4 g or ~ 28% difference.ConclusionsMaternal and neonatal vitamin D status are positively correlated. In this study, maternal adiposity and serum 25(OH)D < 50 nmol/L are dual exposures for neonatal adiposity. These findings reinforce the importance of vitamin D supplementation early in infancy irrespective of vitamin D stores acquired in utero and maternal weight status.
| S-EPMC8801116 | biostudies-literature