BackgroundObservational studies in humans have reported a link between schistosome infection and lower adiposity, but this may be explained by socioeconomic and demographic factors, intensity of... Show moreBackgroundObservational studies in humans have reported a link between schistosome infection and lower adiposity, but this may be explained by socioeconomic and demographic factors, intensity of infection, or common co-infections such as HIV. MethodsThis was a cross-sectional study that investigated the relationship between schistosome infection and adiposity in a large, well-described cohort of Tanzanian adults living with and without HIV. Cross-sectional data were collected among adults living in Mwanza, Tanzania who were enrolled in the Chronic Infections, Co-morbidities and Diabetes in Africa (CICADA) cohort study. Schistosome circulating anodic antigen, secreted by both Schistosoma mansoni and haematobium which are endemic to Tanzania, was quantified from stored samples. Schistosome infection diagnosed by serum circulating anodic antigen levels. The primary outcome was fat mass measured by bioimpedance analysis. Secondary outcomes included fat-free mass, waist circumference, mid-upper arm circumference, and body mass index. ResultsThe study enrolled 1,947 adults, of whom 1,923 (98.8%) had serum available for schistosome testing. Of these, 873 (45.4%) had a serum circulating anodic antigen >= 30 pg/mL, indicating schistosome infection. Compared to uninfected individuals, those with schistosome infections had -1.1 kg [95% CI -1.9 to -0.3] lower fat mass after adjusting for age, sex, physical activity, tobacco use, education level, and socioeconomic status. Infected participants also had lower waist circumference, mid-upper arm circumference, and body mass index. Fat-free mass was not different between the two groups. Neither being HIV-infected, nor receiving antiretroviral therapy, modified associations between schistosome infection and adiposity. These associations were also not affected by Schistosoma worm burden. ConclusionsSchistosome infection was associated with lower fat mass and less central adiposity without a difference in muscle mass, irrespective of confounders, HIV status, or the intensity of schistosome infection. Future studies should adjust for socioeconomic and demographic factors that are associated with schistosome infection and adiposity. Identifying mechanistic pathways by which schistosome infection reduces adiposity while preserving muscle mass could yield new strategies for obesity control and cardiovascular disease prevention. Show less
The substantial increase in the prevalence of non-communicable diseases in Indonesia might be driven by rapid socio-economic development through urbanization. Here, we carried out a longitudinal 1... Show moreThe substantial increase in the prevalence of non-communicable diseases in Indonesia might be driven by rapid socio-economic development through urbanization. Here, we carried out a longitudinal 1-year follow-up study to evaluate the effect of urbanization, an important determinant of health, on metabolic profiles of young Indonesian adults. University freshmen/women in Jakarta, aged 16-25 years, who either had recently migrated from rural areas or originated from urban settings were studied. Anthropometry, dietary intake, and physical activity, as well as fasting blood glucose and insulin, leptin, and adiponectin were measured at baseline and repeated at one year follow-up. At baseline, 106 urban and 83 rural subjects were recruited, of which 81 urban and 66 rural were followed up. At baseline, rural subjects had better adiposity profiles, whole-body insulin resistance, and adipokine levels compared to their urban counterparts. After 1-year, rural subjects experienced an almost twice higher increase in BMI than urban subjects (estimate (95%CI): 1.23 (0.94; 1.52) and 0.69 (0.43; 0.95) for rural and urban subjects, respectively, P-int < 0.01). Fat intake served as the major dietary component, which partially mediates the differences in BMI between urban and rural group at baseline. It also contributed to the changes in BMI over time for both groups, although it does not explain the enhanced gain of BMI in rural subjects. A significantly higher increase of leptin/adiponectin ratio was also seen in rural subjects after 1-year of living in an urban area. In conclusion, urbanization was associated with less favorable changes in adiposity and adipokine profiles in a population of young Indonesian adults. Show less
Panhuis, W.I.H.; Tsaalbi-Shtylik, A.; Schonke, M.; Harmelen, V. van; Pronk, A.C.M.; Streefland, T.C.M.; ... ; Kooijman, S. 2022
DNA damage responses compete for cellular resources with metabolic pathways, but little is known about the metabolic consequences of impaired DNA replication, a process called replication stress.... Show moreDNA damage responses compete for cellular resources with metabolic pathways, but little is known about the metabolic consequences of impaired DNA replication, a process called replication stress. Here we characterized the metabolic consequences of DNA replication stress at endogenous DNA lesions by using mice with a disruption of Rev1, a translesion DNA polymerase specialized in the mutagenic replication of damaged DNA. Male and female Rev1 knockout (KO) mice were compared with wild-type (WT) mice and followed over time to study the natural course of body weight gain and glucose tolerance. Follow-up measurements were performed in female mice for in-depth metabolic characterization. Body weight and fat mass were only increased in female KO mice versus WT mice, whereas glucose intolerance and a reduction in lean mass were observed in both sexes. Female KO mice showed reduced locomotor activity while male KO mice showed increased activity as compared with their WT littermates. Further characterization of female mice revealed that lipid handling was unaffected by Rev1 deletion. An increased respiratory exchange ratio, combined with elevated plasma lactate levels and increased hepatic gluconeogenesis indicated problems with aerobic oxidation and increased reliance on anaerobic glycolysis. Supplementation with the NAD (+) precursor nicotinamide riboside to stimulate aerobic respiration failed to restore the metabolic phenotype. In conclusion, replication stress at endogenous DNA lesions induces a complex metabolic phenotype, most likely initiated by muscular metabolic dysfunction and increased dependence on anaerobic glycolysis. Nicotinamide riboside supplementation after the onset of the metabolic impairment did not rescue this phenotype.NEW & NOTEWORTHY An increasing number of DNA lesions interferes with cellular replication leading to metabolic inflexibility. We utilized Rev1 knockout mice as a model for replication stress, and show a sex-dependent metabolic phenotype, with a pronounced reduction of lean mass and glucose tolerance. These data indicate that in obesity, we may end up in an infinite loop where metabolic disturbance promotes the formation of DNA lesions, which in turn interferes with cellular replication causing further metabolic disturbances. Show less
Context: Follicle-stimulating hormone (FSH) concentrations increase during the perimenopausal transition and remain high after menopause. Loss of bone mineral density (BMD) and gain of bone marrow... Show moreContext: Follicle-stimulating hormone (FSH) concentrations increase during the perimenopausal transition and remain high after menopause. Loss of bone mineral density (BMD) and gain of bone marrow adiposity (BMA) and body fat mass also occur during this time. In mice, blocking the action of FSH increases bone mass and decreases fat mass.Objective: To investigate the associations between endogenous FSH levels and BMD, BMA, and body composition in older adults, independent of estradiol and testosterone levels.Design, Setting, and Participants: Older adults from the AGES-Reykjavik Study, an observational cohort study.Main Outcome Measures: Areal BMD, total body fat, and lean mass were measured with dual-energy x-ray absorptiometry. Lumbar vertebral BMA was measured by H-1-magnetic resonance spectroscopy. Volumetric BMD and visceral and subcutaneous adipose tissue (VAT, SAT) areas were measured with quantitative computed tomography. The least squares means procedure was used to determine sex hormone-adjusted associations between quartiles of serum FSH and BMD, BMA, and body composition.Results: In women (N = 238, mean age 81 years), those in the highest FSH quartile, compared with the lowest quartile, had lower adjusted mean spine integral BMD (-8.6%), lower spine compressive strength index (-34.8%), higher BMA (+8.4%), lower weight (-8.4%), lower VAT (-17.6%), lower lean mass (-6.1%), and lower fat mass (-11.9%) (all P < 0.05). In men, FSH level was not associated with any outcome.Conclusions:Older postmenopausal women with higher FSH levels have higher BMA, but lower BMD and lower fat and lean mass, independent of estradiol and testosterone levels. Longitudinal studies are needed to better understand the underlying mechanisms. Show less
Context: FSH may have independent actions on bone remodeling and body fat regulation. Cross-sectionally, we have shown that serum FSH is associated with bone mineral density (BMD) and body fat in... Show moreContext: FSH may have independent actions on bone remodeling and body fat regulation. Cross-sectionally, we have shown that serum FSH is associated with bone mineral density (BMD) and body fat in older postmenopausal women, but it remains unknown whether FSH predicts bone and fat changes.Objective: We examined whether baseline FSH level is associated with subsequent bone loss or body composition changes in older adults.Setting, Design, Participants: We studied 162 women and 158 men (mean age 82 4 years) from the Age, Gene/Environment Susceptibility (AGES)-Bone Marrow Adiposity cohort, a substudy of the AGES-Reykjavik Study of community-dwelling older adults. Skeletal health and body composition were characterized at baseline and 3 years later.Main Outcomes: Annualized change in BMD and body composition by dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT). Models were adjusted for serum estradiol and testosterone levels.Results: There was no evidence for an association between baseline FSH level and change in BMD or body composition by DXA or QCT. For femoral neck areal BMD, adjusted mean difference (95% CI) per SD increase in FSH was 1.3 (-0.7 to 3.3) mg/cm(2)/y in women, and -0.2 (-2.6 to 2.2) mg/cm(2)/y in men. For visceral fat, adjusted mean difference (95% CI) per SD increase in FSH was 1.80 (-0.03 to 3.62) cm(2)/y in women, and -0.33 (-3.73 to 3.06) cm(2)/y in men.Conclusions: Although cross-sectional studies and studies in perimenopausal women have demonstrated associations between FSH and BMD and body composition, in older adults, FSH level is not associated with bone mass or body composition changes. Show less
Leptin is a hormone which functions in the regulation of energy homeostasis via suppression of appetite. In zebrafish, there are two paralogous genes encoding leptin, called lepa and lepb. In a... Show moreLeptin is a hormone which functions in the regulation of energy homeostasis via suppression of appetite. In zebrafish, there are two paralogous genes encoding leptin, called lepa and lepb. In a gene expression study, we found that the lepb gene, not the lepa gene, was significantly downregulated under the state of insulin-resistance in zebrafish larvae, suggesting that the lepb plays a role in glucose homeostasis. In the current study, we characterised lepb-deficient (lepb(-/)(-)) adult zebrafish generated via a CRISPR-CAS9 gene editing approach by investigating whether the disruption of the lepb gene would result in the development of type 2 diabetes mellitus (T2DM) and diabetic complications. We observed that lepb(-)(/-)adult zebrafish had an increase in body weight, length and visceral fat accumulation, compared to age-matched control zebrafish. In addition, lepb(-/-) zebrafish had significantly higher blood glucose levels compared to control zebrafish. These data collectively indicate that lepb(-/-)adult zebrafish display the features of T2DM. Furthermore, we showed that lepb(-/-) adult zebrafish had glomerular hypertrophy and thickening of the glomerular basement membrane, compared to control zebrafish, suggesting that lepb(-/-) adult zebrafish develop early signs of diabetic nephropathy. In conclusion, our results demonstrate that lepb regulates glucose homeostasis and adiposity in zebrafish, and suggest that lepb(-/-) mutant zebrafish are a promising model to investigate the role of leptin in the development of T2DM and are an attractive model to perform mechanistic and therapeutic research in T2DM and its complications. Show less
Noordam, R.; Huurman, N.C.; Wijsman, C.A.; Akintola, A.A.; Jansen, S.W.M.; Stassen, S.; ... ; Heemst, D. van 2018
