Social stress and recovery: implications for body weight and body composition

Social stress resulting from dominant-subordinate relationships is associated with body weight loss and altered body composition in subordinate (SUB) male rats. Here, we extend these findings to determine whether stress-induced changes in energy homeostasis persist when the social stress is removed, and the animal is allowed to recover. We examined body weight (BW), body composition, and relevant endocrine measures after one or two cycles of 14 days of social stress, each followed by 21 days of recovery in each rat's individual home cage. SUB lost significantly more BW during social housing in a visible burrow system (VBS) compared with dominant (DOM) animals. Weight loss during social stress was attributable to a decrease in adipose tissue in DOM and SUB, with an additional loss of lean tissue in SUB. During both 21-day recovery periods, DOM and SUB regained lost BW, but only SUB were hyperphagic. Following recovery, SUB had a relatively larger increase in adipose tissue and plasma leptin compared with DOM, indicating that body composition changes were dependent on social status. Control animals that were weight matched to SUB or male rats exposed to the VBS environment without females, and that did not form a social hierarchy, did not exhibit changes in body composition like SUB in the VBS. Therefore, chronic social stress causes social status-dependent changes in BW, composition and endocrine measures that persist after repeated stress and recovery cycles and that may ultimately lead to metabolic disorders and obesity.     

Aberrant RNA processing contributes to the pathogenesis of mitochondrial diseases in trans-mitochondrial mouse model carrying mitochondrial tRNALeu(UUR) with a pathogenic A2748G mutation

Mitochondrial tRNAs are indispensable for the intra-mitochondrial translation of genes related to respiratory subunits, and mutations in mitochondrial tRNA genes have been identified in various disease patients. However, the molecular mechanism underlying pathogenesis remains unclear due to the lack of animal models. Here, we established a mouse model, designated ‘mito-mice tRNA^Leu(UUR)2748’, that carries a pathogenic A2748G mutation in the tRNA^Leu(UUR) gene of mitochondrial DNA (mtDNA). The A2748G mutation is orthologous to the human A3302G mutation found in patients with mitochondrial diseases and diabetes. A2748G mtDNA was maternally inherited, equally distributed among tissues in individual mice, and its abundance did not change with age. At the molecular level, A2748G mutation is associated with aberrant processing of precursor mRNA containing tRNA^Leu(UUR) and mt-ND1, leading to a marked decrease in the steady-levels of ND1 protein and Complex I activity in tissues. Mito-mice tRNA^Leu(UUR)2748 with ≥50% A2748G mtDNA exhibited age-dependent metabolic defects including hyperglycemia, insulin insensitivity, and hepatic steatosis, resembling symptoms of patients carrying the A3302G mutation. This work demonstrates a valuable mouse model with an inheritable pathological A2748G mutation in mt-tRNA^Leu(UUR) that shows metabolic syndrome-like phenotypes at high heteroplasmy level. Furthermore, our findings provide molecular basis for understanding A3302G mutation-mediated mitochondrial disorders.