Distinct regulatory mechanisms governing embryonic versus adult adipocyte maturation

Abstract

Pathological expansion of adipose tissue contributes to the metabolic syndrome. Distinct depots develop at various times under different physiological conditions. The transcriptional cascade mediating adipogenesis is established in vitro, and centers around a core program involving PPARγ and C/EBPα. We developed an inducible, adipocyte-specific knockout system to probe the requirement of key adipogenic transcription factors at various stages of adipogenesis in vivo. C/EBPα is essential for all white adipogenic conditions in the adult stage, such as adipose tissue regeneration, adipogenesis in muscle and unhealthy expansion of white adipose tissue during high fat feeding or due to leptin deficiency. Surprisingly, terminal embryonic adipogenesis is fully C/EBPα independent, does depend however on PPARγ; cold-induced beige adipogenesis is also C/EBPα independent. Moreover, C/EBPα is not vital for adipocyte survival in the adult stage. We reveal a surprising diversity of transcriptional signals required at different stages of adipogenesis in vivo.

Emerging Complexities in Adipocyte Origins and Identity

“…It is noteworthy that many lipodystrophy disorders are often characterized by selective adipose tissue atrophy sometimes in combination with compensatory overgrowth in other depots [81], possibly reflecting different origins. Adding to this complexity, emerging evidence also suggests neonatal/juvenile adipogenesis may be mechanistically different from adipogenesis in adults [82, 83]. Characterizing adipocyte development is essential to understanding obesity and those most at risk for obesity-related complications, as well as the set point determinants for white versus brown or brite fat abundance, for which the depot distribution is highly variable in the human population.…”

Functional roles of MMP14 and MMP15 in early postnatal mammary gland development

“…Independent of the effects of MMP14 and MMP15 on mammary epithelial cells, their more global and differential effects on mammary fat pad development were unanticipated. Mmp14 targeting alone triggers a widespread downregulation of transcripts associated with adipogenesis (Wang et al, 2015). By contrast, an Mmp15-null status exerts little effect on white fat development, but instead strongly enhances the formation of brown and/or beige fat, as evidenced by the increased expression of a cohort of thermogenic genes (Wu et al, 2013).…”

“…In an almost diametrically opposed fashion, the metabolic genes repressed in Mmp14 −/− tissue are either upregulated or unchanged in Mmp15-targeted mice, as most clearly evidenced by the differential expression of the adipokine leptin ( Fig. 6D), an adipocyte-derived secreted molecule responsible for regulating tissue metabolism and energy homeostasis (Wang et al, 2015;Wu et al, 2013). Unexpectedly, transcriptome analysis of Mmp15 −/− mammary tissue further reveals a marked increase in a core suite of positive regulators of brown or induced brown (beige) adipocytes (Fig.…”

“…Unexpectedly, transcriptome analysis of Mmp15 −/− mammary tissue further reveals a marked increase in a core suite of positive regulators of brown or induced brown (beige) adipocytes (Fig. S5A) -thermogenic adipocytes that can be identified based on their restricted expression of uncoupling protein 1 (UCP1) (Wang et al, 2015;Wu et al, 2013). Indeed, whereas adipocyte size is unaffected in many regions of the Mmp15 −/− mammary glands, large clusters of small, multilocular adipocytes - the hallmark of beige/brown fat -are found throughout the knockout tissues in four of six animals characterized (Fig.…”

“…In tandem with epithelial development, the surrounding adipose-rich tissue, termed the mammary fat pad, likewise undergoes morphogenesis (Hovey and Aimo, 2010;Inman et al, 2015). Beginning during late gestation (E14 to E18) and continuing through early postnatal development, the fat pad is eventually dominated by committed adipocytes that support epithelial morphogenesis and tissue homeostasis (Wang et al, 2015). At birth, the mammary gland rudiment is a small, simply branched structure that is believed to lie dormant until the onset of puberty (∼3 weeks of age) Hogg et al, 1983;Watson and Khaled, 2008).…”