Developmental programming of offspring adipose tissue biology and obesity risk

Abstract

Obesity is reaching epidemic proportions and imposes major negative health crises and an economic burden in both high and low income countries. The multifaceted nature of obesity represents a major health challenge, with obesity affecting a variety of different organs and increases the risk of many other noncommunicable diseases, such as type 2 diabetes, fatty liver disease, dementia, cardiovascular diseases, and even cancer. The defining organ of obesity is the adipose tissue, highlighting the need to more comprehensively understand the development and biology of this tissue to understand the pathogenesis of obesity. Adipose tissue is a miscellaneous and highly plastic endocrine organ. It comes in many different sizes and shades and is distributed throughout many different locations in the body. Though its development begins prenatally, quite uniquely, it has the capacity for unlimited growth throughout adulthood. Adipose tissue is also a highly sexually dimorphic tissue, patterning men and women in different ways, which means the risks associated with obesity are also sexually dimorphic. Recent studies show that environmental factors during prenatal and early stages of postnatal development have the capacity to programme the structure and function of adipose tissue, with implications for the development of obesity. This review summarizes the evidence for a role for early environmental factors, such as maternal malnutrition, hypoxia, and exposure to excess hormones and endocrine disruptors during gestation in the programming of adipose tissue and obesity in the offspring. We will also discuss the complexity of studying adipose tissue biology and the importance of appreciating nuances in adipose tissue, such as sexual dimorphism and divergent responses to metabolic and endocrine stimuli. Given the rising levels of obesity worldwide, understanding how environmental conditions in early life affects adipose tissue phenotype and the subsequent development of obesity is of absolute importance.

Fig. 1. Molecular pathways controlling the differentiation of mesenchymal cells into brown and white adipocytes.

Diagram depicts key stages in cell differentiation from mesenchymal stem cells to brown and white adipocytes, showing key cell markers at each cell stage. Brown and white adipocytes are derived from mesenchymal stem cells [156] and a number of factors control their differentiation. However, the GSK3β and β-catenin-WNT signaling pathways are particularly important for white adipocyte and brown adipocyte/myocyte lineage commitment, respectively [157]. A zinc finger transcriptional regulator, PRDM16 controls a bidirectional cell fate switch between skeletal myoblasts and brown adipocytes [158]. Differentiation of white adipocytes occurs down a separate lineage and adipogenesis of preadipocytes into mature adipocytes in WAT is controlled by transcriptional regulators, including peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT/enhancer-binding proteins (C/EBPs) [–24]. C/EBPα and C/EBPβ are expressed early in the adipogenesis process along with certain zinc finger proteins, such as ZFP423, they are expressed shortly after commitment to the white adipocyte lineage and subsequently upregulate PPARγ [159]. These molecular factors then operate together to regulate the expression of other adipocyte-specific genes, resulting in the formation of mature adipocytes [159].

Fig. 2. Adipose tissue in different model species.

A Table comparing adipose development in different model species, showing average birth weight, average percentage fat at birth, timing of BAT and WAT development and average percentage fat in species milk composition. B Diagram depicting main adipose storage sites in different model species. VAT visceral adipose tissue, SAT subcutaneous adipose tissue.