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Determinants of intramyocellular lipid accumulation in early childhood.

ABSTRACT: BACKGROUND/OBJECTIVES:Accumulation of lipid droplets inside skeletal muscle fibers (intramyocellular lipids or IMCL) with increasing obesity has been linked to skeletal muscle insulin resistance and risk of type 2 diabetes in both adults and prepubertal children. We aimed to evaluate the associations of race, genotype, prenatal factors, and postnatal factors with IMCL in early childhood. SUBJECTS/METHODS:This study was a secondary analysis performed on the GUSTO birth cohort. Soleus muscle IMCL of 392 children at 4.5 years of age was measured by magnetic resonance spectroscopy, of which usable imaging data were obtained from 277 children (137 Chinese, 87 Malays, and 53 Indians). Metabolic assessments (fasting glucose, insulin, and HOMA-IR) were performed at age 6. RESULTS:The mean IMCL level at 4.5 years was 0.481?±?0.279% of water resonance (mean?±?sd). Corroborating with results from adults, Indian children had the highest IMCL levels compared with Malay and Chinese children. Among the prenatal factors, the rate of gestational weight gain (GWG rate) was associated with offspring IMCL (B?=?0.396 (0.069, 0.724); p?=?0.018). Both race and GWG rate continued to be associated with offspring IMCL even after accounting for current offspring BMI. Postnatally, IMCL was associated with shorter breastfeeding duration (B?=?0.065 (0.001, 0.128); p?=?0.045) and conditional relative weight gain between ages 2 and 3 (B?=?0.052 (0.012, 0.093); p?=?0.012). The associations with postnatal factors were attenuated after adjusting for current offspring BMI. IMCL was positively associated with offspring BMI (B?=?0.028 (0.012, 0.044); p?=?0.001). IMCL levels were not associated with fasting glucose, fasting insulin, and HOMA-IR at age 6. CONCLUSION:This study provides evidence that IMCL accumulation occurs in early childhood and that developmental factors and race are associated with it. We also show that early childhood IMCL accumulation is well tolerated, suggesting that the adverse associations between IMCL and insulin resistance may emerge at older ages.

SUBMITTER: Michael N

PROVIDER: S-EPMC7188663 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Determinants of intramyocellular lipid accumulation in early childhood.

Michael Navin N Gupta Varsha V Sadananthan Suresh Anand SA Sampathkumar Aparna A Chen Li L Pan Hong H Tint Mya Thway MT Lee Kuan Jin KJ Loy See Ling SL Aris Izzuddin M IM Shek Lynette Pei-Chi LP Yap Fabian Kok Peng FKP Godfrey Keith M KM Leow Melvin K-S MK Lee Yung Seng YS Kramer Michael S MS Henry Christiani Jeyakumar CJ Fortier Marielle Valerie MV Seng Chong Yap Y Gluckman Peter D PD Karnani Neerja N Velan S Sendhil SS

International journal of obesity (2005) 20190828 5

<h4>Background/objectives</h4>Accumulation of lipid droplets inside skeletal muscle fibers (intramyocellular lipids or IMCL) with increasing obesity has been linked to skeletal muscle insulin resistance and risk of type 2 diabetes in both adults and prepubertal children. We aimed to evaluate the associations of race, genotype, prenatal factors, and postnatal factors with IMCL in early childhood.<h4>Subjects/methods</h4>This study was a secondary analysis performed on the GUSTO birth cohort. Sole ...[more]

PMID: 31462692

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Project description:BackgroundCancer cachexia is a multifactorial metabolic syndrome characterized by systemic inflammation and ongoing skeletal muscle loss resulting in weakness, poor quality of life, and decreased survival. Whereas lipid accumulation in skeletal muscle is associated with cancer cachexia as well as the prognosis of cancer patients, surprisingly little is known about the nature of the lipids that accumulate in the muscle during cachexia, and whether this is related to inflammation. We aimed to identify the types and distributions of intramyocellular lipids in patients with and without cancer cachexia.MethodsRectus abdominis muscle biopsies were collected during surgery of patients with pancreatic ductal adenocarcinoma (n = 10 without cachexia, n = 20 cachectic without inflammation (CRP < 10 mg/L), n = 10 cachectic with inflammation (CRP ≥ 10 mg/L). L3-CT scans were analysed to assess body composition based on validated thresholds in Hounsfield units (HU). Muscle sections were stained with Oil-Red O and H&E to assess general lipid accumulation and atrophy. Untargeted lipidomic analyses were performed on laser-microdissected myotubes using LC-MS/MS. The spatial distribution of intramyocellular lipids with differential abundance between groups was visualized by mass-spectrometry imaging. Genes coding for inflammation markers and enzymes involved in de novo ceramide synthesis were studied by qPCR.ResultsMuscle radiation attenuation was lower in cachectic patients with inflammation (median 24.3 [18.6-30.8] HU) as compared with those without inflammation (34.2 [29.3-38.7] HU, P = 0.033) or no cachexia (37.4 [33.9-42.9] HU, P = 0.012). Accordingly, intramyocellular lipid content was lower in non-cachectic patients (1.9 [1.6-2.1]%) as compared with those with cachexia with inflammation (5.5 [4.5-7.3]%, P = 0.002) or without inflammation (4.8 [2.6-6.0]%, P = 0.017). Intramyocellular lipid accumulation was associated with both local IL-6 mRNA levels (rs = 0.57, P = 0.015) and systemic CRP levels (rs = 0.49, P = 0.024). Compared with non-cachectic subjects, cachectic patients had a higher relative abundance of intramyocellular glycerophospholipids and a lower relative abundance of glycerolipids. Furthermore, increases in several intramyocellular lipids such as SM(d36:1), PC(34:1), and TG(48:1) were found in cachectic patients with inflammation and correlated with specific cachexia features. Altered intramyocellular lipid species such as PC(34:1), LPC(18:2), and TG(48:1) showed an uneven distribution in muscle sections of cachectic and non-cachectic patients, with areas featuring abundance of these lipids next to areas almost devoid of them.ConclusionsIntramyocellular lipid accumulation in patients with cachexia is associated with both local and systemic inflammation, and characterized by changes in defined lipid species such as glycerolipids and glycerophospholipids.

Project description:Aims/hypothesisPhysical inactivity, low mitochondrial function, increased intramyocellular lipid (IMCL) deposition and reduced insulin sensitivity are common denominators of chronic metabolic disorders, like obesity and type 2 diabetes. Yet, whether low mitochondrial function predisposes to insulin resistance in humans is still unknown.MethodsHere we investigated, in an intervention study, whether muscle with low mitochondrial oxidative capacity, induced by one-legged physical inactivity, would feature stronger signs of lipid-induced insulin resistance. To this end, ten male participants (age 22.4 ± 4.2 years, BMI 21.3 ± 2.0 kg/m2) underwent a 12 day unilateral lower-limb suspension with the contralateral leg serving as an active internal control.ResultsIn vivo, mitochondrial oxidative capacity, assessed by phosphocreatine (PCr)-recovery half-time, was lower in the inactive vs active leg. Ex vivo, palmitate oxidation to 14CO2 was lower in the suspended leg vs the active leg; however, this did not result in significantly higher [14C]palmitate incorporation into triacylglycerol. The reduced mitochondrial function in the suspended leg was, however, paralleled by augmented IMCL content in both musculus tibialis anterior and musculus vastus lateralis, and by increased membrane bound protein kinase C (PKC) θ. Finally, upon lipid infusion, insulin signalling was lower in the suspended vs active leg.Conclusions/interpretationTogether, these results demonstrate, in a unique human in vivo model, that a low mitochondrial oxidative capacity due to physical inactivity directly impacts IMCL accumulation and PKCθ translocation, resulting in impaired insulin signalling upon lipid infusion. This demonstrates the importance of mitochondrial oxidative capacity and muscle fat accumulation in the development of insulin resistance in humans.Trial registrationClinicalTrial.gov NCT01576250.FundingPS was supported by a 'VICI' Research Grant for innovative research from the Netherlands Organization for Scientific Research (Grant 918.96.618).

Project description:Epilepsies of early childhood are frequently resistant to therapy and often associated with cognitive and behavioural comorbidity. Aetiology focused precision medicine, notably gene-based therapies, may prevent seizures and comorbidities. Epidemiological data utilizing modern diagnostic techniques including whole genome sequencing and neuroimaging can inform diagnostic strategies and therapeutic trials. We present a 3-year, multicentre prospective cohort study, involving all children under 3 years of age in Scotland presenting with epilepsies. We used two independent sources for case identification: clinical reporting and EEG record review. Capture-recapture methodology was then used to improve the accuracy of incidence estimates. Socio-demographic and clinical details were obtained at presentation, and 24 months later. Children were extensively investigated for aetiology. Whole genome sequencing was offered for all patients with drug-resistant epilepsy for whom no aetiology could yet be identified. Multivariate logistic regression modelling was used to determine associations between clinical features, aetiology, and outcome. Three hundred and ninety children were recruited over 3 years. The adjusted incidence of epilepsies presenting in the first 3 years of life was 239 per 100 000 live births [95% confidence interval (CI) 216-263]. There was a socio-economic gradient to incidence, with a significantly higher incidence in the most deprived quintile (301 per 100 000 live births, 95% CI 251-357) compared with the least deprived quintile (182 per 100 000 live births, 95% CI 139-233), χ2 odds ratio = 1.7 (95% CI 1.3-2.2). The relationship between deprivation and incidence was only observed in the group without identified aetiology, suggesting that populations living in higher deprivation areas have greater multifactorial risk for epilepsy. Aetiology was determined in 54% of children, and epilepsy syndrome was classified in 54%. Thirty-one per cent had an identified genetic cause for their epilepsy. We present novel data on the aetiological spectrum of the most commonly presenting epilepsies of early childhood. Twenty-four months after presentation, 36% of children had drug-resistant epilepsy (DRE), and 49% had global developmental delay (GDD). Identification of an aetiology was the strongest determinant of both DRE and GDD. Aetiology was determined in 82% of those with DRE, and 75% of those with GDD. In young children with epilepsy, genetic testing should be prioritized as it has the highest yield of any investigation and is most likely to inform precision therapy and prognosis. Epilepsies in early childhood are 30% more common than previously reported. Epilepsies of undetermined aetiology present more frequently in deprived communities. This likely reflects increased multifactorial risk within these populations.

Project description:The preventive effects of regular exercise on obesity-related health problems are carried over to the non-exercise detraining period, even when physical activity decreases with aging. However, it remains unknown whether regular childhood exercises can be carried over to adulthood. Therefore, this study aimed to investigate the effects of long-term childhood exercise and detraining on lipid accumulation in organs to prevent obesity in adulthood. Four-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF) rats were used as obese animals. OLETF rats were allocated into sedentary and exercise groups: exercise from 4- to 12-week-old and detraining from 12- to 20-week-old. At 12-week-old immediately after the exercise period, regular exercise completely inhibited hyperphagia, obesity, enlarged pancreatic islets, lipid accumulation and lobular inflammation in the liver, hypertrophied adipocytes in the white adipose tissue (WAT), and brown adipose tissue (BAT) whitening in OLETF rats. Additionally, exercise attenuated the decrease in the ratio of muscle wet weight to body weight associated with obesity. Decreased food consumption was maintained during the detraining period, which inhibited obesity and diabetes at 20-week-old after the detraining period. Histologically, childhood exercise inhibited the enlargement of pancreatic islets after the detraining period. In addition, inhibition of lipid accumulation was completely maintained in the WAT and BAT after the detraining period. However, the effectiveness was only partially successful in lipid accumulation and inflammation in the liver. The ratio of muscle wet weight to body weight was maintained after detraining. In conclusion, early long-term regular exercise effectively prevents obesity and diabetes in childhood, and its effectiveness can be tracked later in life. The present study suggests the importance of exercise during childhood and adolescence to inhibit hyperphagia-induced lipid accumulation in metabolic-related organs in adulthood despite exercise cessation.

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Determinants of intramyocellular lipid accumulation in early childhood.

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Determinants of intramyocellular lipid accumulation in early childhood.

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