Murine neuronatin deficiency is associated with a hypervariable food intake and bimodal obesity

Irène Cimino ,Samuel Virtue,Richard G Kay,I Sadaf Farooqi,Stephen O’Rahilly,Fiona M Gribble,Pierre Larraufie,Katherine Lawler,J Andrew Pospisilik,Luca Fagnocchi,Y.c Loraine Tung ,Vladimı́r Saudek ,Antonio Vidal–Puig ,Brian Lam ,Giles S.h Yeo ,Kenneth L Marcella ,Ilona Zvetkova,Debra Rimmington,Frank Reimann,Anthony P Coll

doi:10.1038/s41598-021-96278-8

Abstract

Neuronatin (Nnat) has previously been reported to be part of a network of imprinted genes downstream of the chromatin regulator Trim28. Disruption of Trim28 or of members of this network, including neuronatin, results in an unusual phenotype of a bimodal body weight. To better characterise this variability, we examined the key contributors to energy balance in Nnat+/−p mice that carry a paternal null allele and do not express Nnat. Consistent with our previous studies, Nnat deficient mice on chow diet displayed a bimodal body weight phenotype with more than 30% of Nnat+/−p mice developing obesity. In response to both a 45% high fat diet and exposure to thermoneutrality (30 °C) Nnat deficient mice maintained the hypervariable body weight phenotype. Within a calorimetry system, food intake in Nnat+/−p mice was hypervariable, with some mice consuming more than twice the intake seen in wild type littermates. A hyperphagic response was also seen in Nnat+/−p mice in a second, non-home cage environment. An expected correlation between body weight and energy expenditure was seen, but corrections for the effects of positive energy balance and body weight greatly diminished the effect of neuronatin deficiency on energy expenditure. Male and female Nnat+/−p mice displayed subtle distinctions in the degree of variance body weight phenotype and food intake and further sexual dimorphism was reflected in different patterns of hypothalamic gene expression in Nnat+/−p mice. Loss of the imprinted gene Nnat is associated with a highly variable food intake, with the impact of this phenotype varying between genetically identical individuals.

Highlights

Neuronatin (Nnat) has previously been reported to be part of a network of imprinted genes downstream of the chromatin regulator Trim[28]
Nnat deficient mice have a highly variable body weight phenotype that persists on a high fat diet and at thermoneutrality
By 12 weeks of age, there was a significant increase in the variance of body weight in Nnat+/−p mice compared to Nnat+/+ mice (Supplementary Fig. 1C,D). 35% of Nnat+/−p males and 33% of Nnat+/−p females developed obesity (defined as greater than 2 standard deviation (SD) of Nnat+/+ mean) (Supplementary Fig. 1C, D), while the remaining mice displayed a body weight similar to Nnat+/+

Summary

Introduction

Neuronatin (Nnat) has previously been reported to be part of a network of imprinted genes downstream of the chromatin regulator Trim[28]. Disruption of Trim[28] or of members of this network, including neuronatin, results in an unusual phenotype of a bimodal body weight. To better characterise this variability, we examined the key contributors to energy balance in Nnat+/−p mice that carry a paternal null allele and do not express Nnat. Consistent with our previous studies, Nnat deficient mice on chow diet displayed a bimodal body weight phenotype with more than 30% of Nnat+/−p mice developing obesity. In a follow up study of mice carrying the same mutant allele, adult Nnat+/−p mice did display a bimodal body weight phenotype, albeit one with a subpopulation of lean, as opposed to obese, m ice[20]. When the mutant allele was studied in a 129S2/Sv background, mice deficient in Nnat displayed both postnatal growth restriction with diminished adiposity and an obesity phenotype in adulthood

Methods

Results

Conclusion