Paternal Hyperglycermia In Rats Exacerbates The Development Of Obesity In Offspring Involving Reprogramming Hypothalamic Leptin Signaling

Aims/hypothesis: Parental history with obesity or diabetes will increase the risk for developing metabolic diseases in offspring.However,literatures as to transgenerational inheritance of metabolic dysfunctions through male lineage are relatively scarce.In current study,we aimed to evaluate the influences of paternal hyperglycermia on body mass,food intake,brown adipose tissue thermogenic capacity,and hypothalamic leptin signaling and appetite-regulating neurotransmitters in offspring.Methods: Male SD rats were ip injected with streptozotocin(STZ)or citrate buffer(CB)as a control.STZ-injected rats with glucose levels higher than 16.7 m M were selected to breed with normal female rats.Offspring from STZ or CB treated fathers(STZ-O and CB-O)were maintained in the identical condition.We monitored body weight and food intake,tests of fasting-refeeding and cold(4oC)exposure were performed.Expression of factors involved in hypothalamic feeding and brown adipose tissue(BAT)thermogenic activity was performed by real-time PCR and Western blot.Results: Adult STZ-O were heavier than CB-O.Daily food intake and accumulated food intake during 12-hr refeeding after fasting was significantly higher in STZ-O.After cold challenge,m RNA levels of thermogenesis-related genes and UCP1 protein levels were down-regulated in BAT from STZ-O.Finally,STZ-O rats showed suppressed leptin signaling in the hypothalamus as evidenced by upregulated SOCS3,reduced phosphorylation of STAT3,impaired processing POMC and decreased ?-MSH production.Conclusions/interpretation: Our study revealed that paternal hyperglycermia predisposes the offspring to developing obesity,which is possibly associated with impaired hypothalamic leptin signaling.