Neuregulin 1 affects leptin levels, food intake and weight gain in normal-weight, but not obese, db/db mice

Abstract

Aim. -Studies in vitro have highlighted the potential involvement of neuregulin 1 (NRG1) in the regulation of energy metabolism. This effect has also been suggested in vivo, as intracerebroventricular injection of NRG1 reduces food intakes and weight gain in rodents. Thus, it was hypothesised that NRG1 might affect serum leptin levels in mice.Methods. -Weight, food intakes, energy expenditure, spontaneous physical activity and serum leptin levels were evaluated in normal-weight C57BL/6JRJ mice following intraperitoneal administration of NRG1 (50 g/kg, three times/week) or saline for 8 weeks. Based on the results of this first experiment, leptin-resistant obese db/db mice were then given NRG1 for 8 weeks.Results. -Leptin serum concentrations were six times higher in C57BL/6JRJ mice treated with NRG1 than in the animals given saline. NRG1 treatment also reduced weight gain by 10% and food intakes by 15% compared with saline treatment, while energy expenditure remained unchanged. In db/db mice, serum leptin concentrations, weight gain, food intakes, energy expenditure and spontaneous physical activity were not altered by NRG1 treatment.Conclusion. -The decrease in food intakes and weight gain associated with NRG1 treatment in C57BL/6JRJ mice may be partly explained by increased leptin levels, whereas db/db mice were not affected by the treatment, suggesting resistance to NRG1 in this pathological state.

Genome wide association study in 3,173 outbred rats identifies multiple loci for body weight, adiposity, and fasting glucose

“…Nrg1 mediates cell-cell signaling and plays a critical role in growth and development of multiple organ systems. ICV injection of Nrg1 leads to increased food intake and weight gain in rodents (Ennequin et al 2015) and a recent study has demonstrated positive metabolic effect of Nrg1 on multiple metabolic parameters, including body weight ). In addition, Nrg1 has been associated with BMI in a Korean population (Lee et al 2016),…”

Epigenetic regulation of Neuregulin-1 tunes white adipose stem cell differentiation

“…The identification of NRG1 as a key regulator of adipose expansion may provide a novel therapy for obesity. Wild-type mice treated with injections of recombinant NRG1 display metabolic benefits including lowered bodyweight and reduction in percent body fat relative to controls [33] . NRG1 also improved cardiovascular function and attenuated nephropathy in an apoE mutant mouse model [34] .…”

“…When NRG1 was used in clinical trials for human heart failure [31,32] no effect on bodyweight was noted; however, the human therapies were brief, 10 -11 days, whereas the mouse studies took 8 weeks. Despite multiple studies of systemic administration of recombinant NRG1 in rodents, all of which demonstrated positive metabolic effects [33][34][35][36][37] , no study has examined its role in adipose expansion directly. This is even more surprising given that NRG1 administration in mice caused a dramatic spike in leptin, an adipocyte-secreted hormone [33] .…”

“…Despite multiple studies of systemic administration of recombinant NRG1 in rodents, all of which demonstrated positive metabolic effects [33][34][35][36][37] , no study has examined its role in adipose expansion directly. This is even more surprising given that NRG1 administration in mice caused a dramatic spike in leptin, an adipocyte-secreted hormone [33] . Elevated levels of leptin in mouse models promotes reductions in body weight through its effects on the leptin receptor in critical brain regions that regulate food intake and energy expenditure [38] .…”

“…In this model, the function of NRG1 is identical to previously published roles positively regulating stem-cell differentiation [22,24] . While this model was developed from in vitro data, it explains the dramatic rise in leptin (a primarily adipocyte-secreted hormone) upon administration of NRG1 to wild-type mice [33] ; it also may help account for the positive metabolic effects of NRG1 administration to rats [36] , hamsters [37] and an obese mouse model [35] . An important direction for future research is to test the model in a rodent by administering NRG1 protein and testing directly for increased adipose expandability, with the ultimate goal of developing therapies for human metabolic syndrome.…”