Subcutaneous Fat: Thermogenesis and Metabolic Benefits

Abstract

Obesity and its associated metabolic diseases present a major public health problem around the world. The discovery that thermogenic fat is active in adult humans has sparked a renewal of interest in the study of its development and function and in the feasibility of using modulators of thermogenesis to work against obesity. In recent years there have been a number of exciting discoveries about the properties of thermogenic fat, and every new discovery demonstrates just how much we still don’t understand about these cells. Research that gains further understanding through the development of tools or the identification of novel compounds that regulate thermogenic adipocytes may lead to novel therapeutics to target thermogenic fat and could have a profound impact on the efforts to harness the power of thermogenic fat to counteract obesity.

It has long been recognized that body fat distribution and regional adiposity play a major role in the control of metabolic homeostasis. However, the ability to study and compare the cell autonomous regulation and response of adipocytes from different fat depots has been hampered by the difficulty of inducing preadipocytes isolated from the visceral depot to differentiate into mature adipocytes in culture. In the first part of my thesis work, I present an easily created 3D culture system that can be used to differentiate preadipocytes from the visceral depot as robustly as those from the subcutaneous depot. The cells differentiated in these 3D collagen gels are mature adipocytes that retain depot-specific characteristics, as determined by imaging, gene expression, and functional assays. This 3D culture system therefore allows for study of the development and function of adipocytes from both depots in vitro, and may ultimately lead to a greater understanding of site-specific functional differences of adipose tissues to metabolic dysregulation.

Cinnamaldehyde (CA) is a food compound that has previously been observed to be protective against obesity and hyperglycemia. In the second part of my thesis work, I report that CA activates a thermogenic response via PKA signaling in murine subcutaneous adipocytes and that chronic CA treatment induces metabolic reprogramming that is partially dependent on FGF21 and that may contribute to improving whole-body metabolic health. This phenomenon is fat cell-autonomous and well conserved in human adipose stem cells isolated from subcutaneous depots of multiple donors of different ethnicities and ages and with a variety of body mass indexes (BMI). Given the wide usage of cinnamon in the food industry, the notion that this popular food additive, instead of a drug, may activate thermogenesis, could ultimately lead to therapeutic strategies against obesity that are much better adhered to by participants.

The potential of the adipocyte in the understanding and treatment of human physiology in health and disease is clearly as of yet not fully realized. Here, I have provided a method to further study the differences between subcutaneous and visceral fat as well as investigated the pathways through which novel compounds can activate thermogenesis and metabolic reprogramming in murine and human subcutaneous adipocytes. A growing body of research has begun to show that the activation of human thermogenic fat can have a meaningful effect on human physiology, this tangible translational aspect of thermogenic adipocyte research gives promise to the idea that the tools developed here lay ground for further exciting discoveries that are yet to come.