The Thermogenic Circuit: Regulators of Thermogenic Competency and Differentiation

Abstract

In mammals, a thermogenic mechanism exists that increases heat production and consumes energy. Recent work has shed light on the cellular and physiological mechanisms that control this thermogenic circuit. Thermogenically active adipocytes, namely brown and closely related beige adipocytes, differentiate from progenitor cells that commit to the thermogenic lineage but can arise from different cellular origins. Thermogenic differentiation shares some features with general adipogenesis, highlighting the critical role that common transcription factors may play in progenitors with divergent fates. However, thermogenic differentiation is also discrete from the common adipogenic program and, excitingly, cells with distinct origins possess thermogenic competency that allows them to differentiate into thermogenically active mature adipocytes. An understanding of this thermogenic differentiation program and the factors that can activate it has led to the development of assays that are able to measure thermogenic activity both indirectly and directly. By combining these assays with appropriate cell models, novel therapeutic approaches to combat obesity and its related metabolic disorders by enhancing the thermogenic circuit can be developed.

Keywords: Adipogenesis; UCP1; adipocyte; autologous transplants; brown adipose tissue; cell therapy; differentiation; metabolic syndrome; obesity; preadipocyte; thermogenesis.

Figure 1

The basic principle of UCP1 mediated thermogenesis compared to a car engine. Your car engine normally combusts gasoline to release CO₂ and H₂O inside of an enclosed engine cylinder. The gas released pushes up on a piston, sending its energy to the wheels so you can drive forward. Similarly, mitochondria shuttle metabolites through the ETC to store protons on one side of the inner mitochondrial membrane to generate an electrochemical gradient. The protons can pass down this gradient through an ATPase, which uses the proton motive force as energy to phosphorylate ADP, generating ATP. Just as drilling a hole in the engine cylinder would allow the gas produced by combustion to escape without pushing the piston, UCP1 is a channel that allows protons to pass down their electrochemical gradient without activating ATP production. This energy from the proton motive force is instead dissipated as heat, much like your car engine would heat up with holes drilled in the engine cylinders.

Figure 2

Thermogenic differentiation. Thermogenic mature adipocytes arise from both Myf5-positive and Myf5-negative lineages that express a commitment gene program as they differentiate into committed precursor cells. This differentiation program has both aspects common to brown, beige and white preadipocytes as well as aspects distinct to thermogenically competent preadipocytes and can be enhanced by treatment with BMP7 or some members of the FGF family of proteins. Committed thermogenic precursor cells can further differentiate into mature adipocytes by activating a gene network that also shares common features with white adipogenesis, however, distinct thermogenic differentiation factors are also shared between brown and beige adipocytes. This process can also be enhanced by a large group of diverse activators of thermogenic differentiation. Finally, mature thermogenic adipocytes that express UCP1 can be further activated, yet distinct lineage specific markers that distinguish brown, beige and white adipocytes exist.

Figure 3

Assaying the thermogenic circuit. (A) Adipogenic differentiation in vitro can be approximately divided into three phases: commitment, differentiation and maturity. Treatment with reagents that enhance each phase must be carried out in the appropriate treatment window. (B) The thermogenic circuit at the cellular level is composed of the metabolic flux through the cell that generates a proton motive force, which can either be used to generate ATP or uncoupled to generate heat. To measure the activity of the cellular thermogenic circuit, influencing factors such as substrate availability, metabolic enzyme activity, mitochondrial dynamics and UCP1 expression are often measured using a broad range of different assays.

Figure 4

Therapeutic interventions to enhance the thermogenic circuit. Two different basic types of therapy for enhancing the thermogenic circuit in man are possible. First, non cell-based therapies such as drugs, exercise, diet and therapeutic cold exposure are possible. Second, cell-based therapies rely on adipose tissue biopsy to provide SVF cells, which can be used to produce thermogenically competent preadipocytes ex vivo using either drug treatment of cell sorting strategies. These cells can be expanded and differentiated to produce large amounts of thermogenic adipocytes for autologous transplantation back into the donor. Treatment of cells with activators of thermogenic competency and differentiation ex vivo limits potential side effects of treatments on the rest of the body.