| Chapter I.The effect of paternal obesity on offspring metabolism:a prospective studyObjective:Nowadays,the obesity epidemic continues to worsen worldwide,leading to increased risks for many diseases,including cardiovascular disease,type 2 diabetes,and cancer.Besides the adverse effects on personal health in individuals with obesity,growing evidence showed a transmitted effect of parental obesity on their offspring.The adverse effects of paternal obesity on offspring growth and insulin homeostasis have been reported,especially in animal studies.However,few cohort studies related to this phenomenon in humans,and the sex-specific impact of paternal obesity on different remains controversial.The objectives of this study are to clarify the transmitted effect of paternal obesity on glucose and lipid metabolism in offspring and to explore the sex-specific effect of paternal obesity under different nutritional conditions.Methods:This study is a prospective cohort study.A total of 1647 father-offspring follow-up visits were included,including 686 visits of paternal overweight or obesity(Body mass index,BMI>25kg/m2)and 951 visits of their lean counterparts(normal control,BMI<25kg/m2).Firstly,we compared the glucose and lipid metabolism parameters between total offspring with paternal overweight/obesity and their lean counterparts.Then we divided offspring into two groups based on sex to explore the sex-specific effect of paternal overweight/obesity.Furthermore,we examined the impact of paternal overweight/obesity in different calorie intake conditions on male and female offspring.The glucose metabolism parameters included fasting glucose,fasting insulin,homeostasis model assessment of insulin resistance(HOMA-IR),and homeostasis model assessment of pancreatic beta-cell function(HOMA-B).The lipid metabolism parameters included triglyceride(TG),cholesterol(CHOL),low-density lipoprotein cholesterol(LDL-C),and high-density lipoprotein cholesterol(HDL-C).Continuous data in normality distribution were expressed as mean ± standard deviation,and data in non-normality distribution were presented as median(the 25th percentile,the 75th percentile).Given it is a repeated measure study design,we fit the linear mixed model to the data,and the non-normally distributed data were put after natural logarithmic transformation.We used R3.6.1 for statistical analysis.Results:The fasting glucose and insulin levels,HOMA-IR and TG were significantly higher in total offspring with paternal overweight/obesity than with their lean counterparts[main effect:fasting glucose:5.09 ± 0.39 vs.5.04 ± 0.40,mean difference(MD):0.07,95%confidence interval(CI):0.03-0.11,insulin:5.72(3.61,8.34)vs 5.14(3.41,7.61),MD:0.13,95%CI:0.06-0.19,HOMA-IR:1.30(0.81,1.95)vs 1.17(0.73,1.76),MD:0.14,95%CI:0.07-0.21,TG:0.70(0.56,0.92)vs 0.68(0.55,0.86),MD:0.04,95%CI:0.01-0.08].In female offspring,significant differences were reached in fasting glucose,fasting insulin and HOMA-IR between paternal overweight/obesity group and their lean counterparts(main effect:fasting glucose:5.05±0.41 vs 4.99±0.39,MD:0.07,95%CI:0.01-0.13,insulin:5.94[3.60,8.63]vs 5.16[3.53,7.48],MD:0.14,95%CI:0.05-0.23);HOMA-IR:1.33[0.79,2.00]vs 1.14[0.75,1.71],MD:0.15,95%CI:0.06-0.25).No difference was found in lipid parameters between paternal overweight/obesity group and their lean counterparts in female offspring.We also found significant difference of these glucose parameters in high calories intake condition in female offspring[fasting glucose:5.09±0.41 vs 4.99±0.40,MD:0.10,95%CI:0.02-0.18;insulin:6.82(4.14,9.83)vs 5.57(3.61,7.69),MD:0.17,95%CI:0.05-0.29;HOMA-IR:1.58(0.84,2.35)vs 1.20(0.78,1.76),MD:0.19,95%CI:0.06-0.32],but not in low calories intake condition.In male offspring,the fasting glucose,fasting insulin,HOMA-IR and TG were significantly increased in paternal overweight/obesity group than their lean counterparts(main effect:fasting glucose:5.14±0.36 vs 5.10±0.40,MD:0.08,95%CI:0.02-0.13,insulin:5.40[3.70,8.16]vs 5.14[3.37,7.73],MD:0.11,95%CI:0.02-0.20,HOMA-IR:1.25[0.82,1.86]vs 1.17[0.73,1.79],MD:0.12,95%CI:0.03-0.22,TG:0.69[0.55,0.92]vs 0.66[0.53,0.84],MD:0.06,95%CI:0.01-0.12).However,only fasting glucose level was significantly higher than their lean counterparts in high calories condition[5.19±0.32 vs.5.13±0.43,MD:0.10,95%CI:0.02-0.18],no difference was found in insulin,HOMA-IR and TG between paternal obesity and their lean counterparts in both high and low calories intake conditions.Conclusion:Paternal obesity impaired glucose and lipid homeostasis in their offspring.Female offspring was more sensitive than male offspring after paternal obesity exposure in glucose homeostasis,especially in high calories intake conditions.However,paternal obesity results in a higher TG level in male but not female offspring.Chapter II.Influence of paternal obesity on peripheral blood inflammation of offspringObjective:Over the last two decades,it has been widely demonstrated that obesity is associated with chronic low-grade inflammation.This kind of immune disorder may serve as a causal relationship between obesity and insulin resistance.It has been proved that parental immune disorder could be transmitted to their next generation,and early-life programmed immune dysfunction will results in an increased risk of many diseases,both in childhood and adulthood.Up to now,the effect of paternal obesity on offspring immune dysfunction and related inflammation hasn't been reported.The purpose of this study is to address the potential impact of paternal obesity on inflammation of peripheral T cell subsets in their early childhood offspring.Methods:This study is a case-control study.A total of 95 offspring aged 2-7 years were recruited,including 48 offspring with paternal overweight/obesity(BMI>25kg/m2)and 47 offspring with their lean counterparts(normal control,BMI<25kg/m2).The peripheral blood mononuclear cell(PBMC)were isolated from peripheral blood,and then the proportions of CD4+CD25+CD127low regulatory T cells(Tregs),CD3+CD4+IFNy+Thl cells,CD3+CD4+IL-17+Th17 cells and CD3+CD4+IL22+Th22 cells in the peripheral blood were identified by flow cytometry.Besides,leptin,adiponectin,inflammatory cytokines including IL-6,IL-8,TNA-a and IL-1b,and chemokines including CCL-5 and MCP-1 were measured in plasma of female offspring by enzyme-linked immunosorbent assay(ELISA).Results:The proportion of Treg was significantly lower in total offspring and female offspring with paternal overweight/obesity than with their lean counterparts(total offspring:3.32±2.22 vs.4.73±3.01,p=0.01;female offspring:3.06±1.85 vs.5.42±3.25,p<0.01),but was not altered between groups in male offspring.The trajectory showed that female offspring with paternal overweight/obesity had a lower level of Treg cells than their lean counterparts at each age from 2-7.The proportion of IFN?+Th1 cells tended to be higher in female offspring with paternal overweight/obesity(7.97±5.69 vs.5.12±3.19,p=0.09),but no difference was found in total and male offspring.It should be noticed that the difference in IFN-?+Th1 cells between female offspring with paternal overweight/obesity and their lean counterparts increased with age.No differences were found in Th 17 cells and Th22 cells in offspring between groups.Plasma leptin level was significantly higher in female offspring with paternal obesity than their lean counterparts.There were no differences in plasma levels of adiponectin other inflammatory chemokines and cytokines.Conclusion:Female offspring with paternal obesity in humans had a decrease of circulating Tregs and an increase of Thl cells,which may indicate a pro-inflammatory immune response in T cells.Chapter ?.Paternal obesity influences immune cell populations in offspring adipose tissue and its related inflammation in early adulthood miceObjective:Obesity is characterized as an excessive amount of body fat.In normal conditions,macrophages reside in adipose tissue(AT).In stress conditions,resident macrophages produce increased amounts of signals to defense and remove the apoptotic cells.When the stress pressure is extreme,the response of local resident macrophages may be insufficient,and AT can recruit additional macrophages from blood.In obesity,macrophages,T cells,and other immune cells are increased in AT and play a central role in development of insulin resistance.Thus,it is vital to improve our understanding of the transmitted effects of paternal obesity on adipose tissue immune cells and inflammatory response.The objective of this study is to explore the impact of paternal obesity on the modulation of immune cell populations and related inflammation in AT of offspring in mice at early adulthood.Method:Male C57BL/6J mice were fed either a western-type high-fat diet(WD)or low-fat chow diet(CD)for 3 months before mating with female C57BL/6J mice fed CD.At 3 weeks old,offspring were weaned onto CD or WD to generate four different groups based on paternal/offspring diets:Paternal obesity(PO)/offspring CD group,paternal control Con)/offspring CD group,paternal PO/offspring WD group,and paternal Con/offspring WD group.We performed intraperitoneal glucose tolerance test(IPGTT)when the offspring were 7 weeks old.Offspring were sacrificed at the age of 8 weeks and perigonadal visceral AT(PAT),and inguinal subcutaneous AT(SAT)were collected to examine macrophages and dendritic cells(M(p/DCs),T cells,and eosinophils through flow cytometry.Results:In IPGTT,female offspring of paternal obesity compared to their lean counterpart had impaired glucose tolerance in both postnatal CD and WD condition.However,male offspring of paternal obesity had decreased glucose area under the curve(GAUC)than their lean counterparts in postnatal CD condition.No difference was found when introduced to postnatal WD condition.In postnatal CD condition,the number of Mcp/DCs in SAT was reduced in female offspring in response to paternal WD exposure(PO/CD vs.Con/CD),which is similar with female offspring of control group as a result of postnatal WD exposure(Con/WD vs.Con/CD).Then,female offspring of paternal obesity had a significantly decreased Mcp/DCs in PAT as a result of postnatal WD exposure(PO/WD vs.PO/CD).In male offspring,the numbers of M?/DCs and T cells were significantly increased in SAT,and M?/DCs were decreased in PAT in male offspring in response to paternal WD exposure(PO/CD vs.Con/CD),which is similar with male offspring of control group as a result of postnatal WD exposure(Con/WD vs.Con/CD).Then,male offspring of paternal obesity had a significantly decreased M?/DCs in SAT after postnatal WD exposure(PO/WD vs.PO/CD).No difference of immune cell populations in PAT in male offspring of paternal obesity after postnatal WD exposure(PO/WD vs.PO/CD).We found a significantly higher proportion of CD11c+CD206low Ml-like Mcp/DCs within total Mcp/DCs in PO/CD than Con/CD in both PAT and SAT of female and male offspring.The proportion of IL-12-expressing cells in CD11c+CD206low M?/DCs was significantly higher in female offspring of paternal obesity in both PAT and SAT in postnatal CD condition.No difference was found between paternal obesity and their lean counterparts in postnatal WD condition in female offspring.However,in male offspring,no difference was found in IL-12 expression in CD11c+CD206low M?/DCs in postnatal CD condition regardless of AT depots.When introduced to postnatal WD,the proportion of CD11c+CD206low M?/DCs was significantly higher in PAT,but not SAT,in PO/WD group compared with Con/WD group.Conclusion:Paternal obesity influences immune cell populations in offspring AT in early adulthood.Paternal obesity results in higher CD11c+CD206low M?/DCs,which exhibit a proinflammatory phenotype in AT of offspring,particularly female offspring on CD.The increased immune cells may play a protective role in glucose homeostasis in male offspring of paternal obesity in their early adulthood on CD.However,when introduced to postnatal WD condition,the inflammatory response of immune cells in PAT of offspring may contribute to the impairment of glucose tolerance. |
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