Accelerated developmental adipogenesis programs adipose tissue dysfunction and cardiometabolic risk in offspring born to dams with metabolic dysfunction.

Anna Mikolajczak,Nada A Sallam,Taylor B Scheidl,Carol Huang,Emma J Walsh,Jennifer A Thompson,Radha D Singh,Sebastian Larion

doi:10.1152/ajpendo.00229.2021

Abstract

This study determined if a perturbation in in utero adipogenesis leading to later life adipose tissue (AT) dysfunction underlies programming of cardiometabolic risk in offspring born to dams with metabolic dysfunction. Female mice heterozygous for the leptin receptor deficiency (Hetdb) had 2.4-fold higher prepregnancy fat mass and in late gestation had higher plasma insulin and triglycerides compared with wild-type (Wt) females (P < 0.05). To isolate the role of the intrauterine milieu, wild-type (Wt) offspring from each pregnancy were studied. Differentiation potential in isolated progenitors and cell size distribution analysis revealed accelerated adipogenesis in Wt pups born to Hetdb dams, accompanied by a higher accumulation of neonatal fat mass. In adulthood, whole body fat mass by NMR was higher in male (69%) and female (20%) Wt offspring born to Hetdb versus Wt pregnancies, along with adipocyte hypertrophy and hyperlipidemia (all P < 0.05). Lipidomic analyses by gas chromatography revealed an increased lipogenic index (16:0/18:2n6) after high-fat/fructose diet (HFFD). Postprandial insulin, ADIPO-IR, and ex vivo AT lipolytic responses to isoproterenol were all higher in Wt offspring born to Hetdb dams (P < 0.05). Intrauterine metabolic stimuli may direct a greater proportion of progenitors toward terminal differentiation, thereby predisposing to hypertrophy-induced adipocyte dysfunction.NEW & NOTEWORTHY This study reveals that accelerated adipogenesis during the perinatal window of adipose tissue development predisposes to later life hypertrophic adipocyte dysfunction, thereby compromising the buffering function of the subcutaneous depot.

Highlights

Since the 1970s, obesity rates among women of reproductive age have more than tripled, reaching over 50% in certain sociodemographic groups [1, 2]
Whole body composition analysis by NMR spectroscopy revealed that prepregnancy fat mass was 2.4-fold higher and lean body mass 13% lower in Hetdb versus Wt females (P < 0.0001)
The Hetdb female recapitulates central features of human pregnancies complicated by maternal obesity and GDM, including high prepregnancy adiposity, hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia

Summary

Introduction

Since the 1970s, obesity rates among women of reproductive age have more than tripled, reaching over 50% in certain sociodemographic groups [1, 2]. Prepregnancy obesity and hypertriglyceridemia are strong predictors of gestational diabetes (GDM), which occurs in 18% of pregnancies worldwide and up to 25% in certain North American populations [3, 4]. These trends have made maternal metabolic disorders the most common complications of pregnancy. In utero transmission may be a critical driver of metabolic disease and its declining age of onset Both human and animal studies have established an association between maternal metabolic dysfunction and cardiometabolic risk in the offspring, the underlying developmental mechanisms remain incompletely understood

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