Loss of Uncoupling Protein 1 Expression in the Subcutaneous Adipose Tissue Predicts Childhood Obesity

Abstract

Stimulation of thermogenesis by inducing uncoupling protein 1 (UCP1) expression in adipocytes is thought to promote weight loss by increasing energy expenditure, and it is postulated that the human newborn has thermogenic subcutaneous fat depots. However, it remains unclear whether a relevant number of UCP1-expressing (UCP1+) adipocytes exist in the early postnatal life. Here we studied the distribution of UCP1 and the expression of thermogenic genes in the subcutaneous adipose tissues of the human fetus, infant and child. We show that the deep layer of human fetal and neonatal subcutaneous fat, particularly the abdominal wall, is rich in UCP1+ adipocytes. These adipocytes develop in the late third trimester and persist throughout childhood, expressing a panel of genes linked to mitochondrial biogenesis and thermogenesis. During the early childhood adiposity rebound—a critical phase that determines obesity risk later in life—the absence of adipose tissue UCP1 expression in children with normal body mass index (BMI) correlates with an obesity-associated gene expression signature. Finally, UCP1 expression is negatively correlated with BMI z-score and adipocyte size in infants and children. Overall, our results show that the absence of UCP1 expression in adipose tissue is an early indicator of adipose tissue expansion in children.

Interleukin-6: An Under-Appreciated Inducer of Thermogenic Adipocyte Differentiation

“…The abundance of mitochondria combined with the expression of UCP1 evokes thermogenic potential in adipocytes, which eventually allows non-shivering thermogenesis, protects the core body temperature, and increases energy expenditure [ 37 ]. The loss of thermogenic adipocytes appears in aging and in obesity and is associated with worsened insulin sensitivity and glycemic control [ 38 , 39 ].…”

“…The gene network includes Ucp1 , encoding uncoupling protein 1; Ppargc1a , encoding peroxisome proliferator activated receptor gamma coactivator 1; Cidea , encoding cell death-inducing DFFA-like effector A; Prdm16 , encoding PR domain containing 16; Dio2 , encoding Type II iodothyronine deiodinase; and Cox7a1 , encoding cytochrome c oxidase subunit 7A1. Moreover, Lhx8 and Myod1 , which encode proteins (LIM homeobox 8 and myogenic differentiation 1, respectively) involved in thermogenic adipocyte development, are also associated with the gene network [ 39 , 92 ]. ( b ) Scheme summarizing transcription binding sites upstream to promoter regions of Ucp1 , Ppargc1a , Cidea , Cox7a1 , Dio2 , Myod1 and Lhx8 .…”

Metabolic Effects of Brown Adipose Tissue Activity Due to Cold Exposure in Humans: A Systematic Review and Meta-Analysis of RCTs and Non-RCTs

“…BAT is a highly specialized type of fat tissue mainly found in newborns of mammals and human infants, whose primary functions involve non-shivering thermogenesis (NST) [ 10 ] and the production of heat to maintain normal body temperature [ 11 ]. Breastfeeding plays an important role in the development of thermogenic fat in human newborns [ 12 , 13 , 14 ]. After birth, maternal cues including free fatty acids (FFAs) and alkylglycerols are delivered through milk [ 12 , 15 ] and microbial products of the gut microbiota to infants [ 16 ], which triggers thermogenic (beige/brown) fat development.…”

“…Breastfeeding plays an important role in the development of thermogenic fat in human newborns [12][13][14]. After birth, maternal cues including free fatty acids (FFAs) and alkylglycerols are delivered through milk [12,15] and microbial products of the gut microbiota to infants [16], which triggers thermogenic (beige/brown) fat development.…”