Abstract
Maternal obesity (MO) predisposes offspring to obesity and metabolic disorders but little is known about the contribution of offspring brown adipose tissue (BAT). We find that MO impairs fetal BAT development, which persistently suppresses BAT thermogenesis and primes female offspring to metabolic dysfunction. In fetal BAT, MO enhances expression of Dio3, which encodes deiodinase 3 (D3) to catabolize triiodothyronine (T3), while a maternally imprinted long noncoding RNA, Dio3 antisense RNA (Dio3os), is inhibited, leading to intracellular T3 deficiency and suppression of BAT development. Gain and loss of function shows Dio3os reduces D3 content and enhances BAT thermogenesis, rendering female offspring resistant to high fat diet-induced obesity. Attributing to Dio3os inactivation, its promoter has higher DNA methylation in obese dam oocytes which persists in fetal and adult BAT, uncovering an oocyte origin of intergenerational obesity. Overall, our data uncover key features of Dio3os activation in BAT to prevent intergenerational obesity and metabolic dysfunctions.
Highlights
Maternal obesity (MO) predisposes offspring to obesity and metabolic disorders but little is known about the contribution of offspring brown adipose tissue (BAT)
MO female offspring had similar caloric intake compared to CON offspring but gained more body mass (Fig. 1b, c), and demonstrated glucose intolerance and insulin resistance compared with CON offspring (Fig. 1d, e)
The reduction of energy expenditure was worsened by accounting for body fat (Fig. 1g and Supplemental Fig. 3a, c and d), aligned with reduced core and surface body temperatures (Fig. 1h and Supplemental Fig. 3e, f), suggesting metabolic dysfunction of thermogenic fat
Summary
Maternal obesity (MO) predisposes offspring to obesity and metabolic disorders but little is known about the contribution of offspring brown adipose tissue (BAT). We find that MO impairs fetal BAT development, which persistently suppresses BAT thermogenesis and primes female offspring to metabolic dysfunction. In the United States, more than two-thirds of women of reproductive age are either obesity or overweight[2]. Brown fat (BAT) is a key tissue for thermogenesis and protects humans and mice from obesity and metabolic dysfunctions[7,8]. In humans and mice, impaired BAT thermogenesis leads to obesity, metabolic dysfunctions, and aging, whereas thermogenic activation enhances weight loss and insulin sensitivity[7,8]. The BAT thermogenesis is inducible, notably by cold stimulus, which depends on de novo formation of brown adipocytes from progenitor cells[9], which have fetal origins[10]. A set of master regulatory genes, including Prdm[16] and Ebf[2], commit these progenitor cells to the brown adipocyte lineage[11,12]
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