Thermogenic T cells: a cell therapy for obesity?

Abstract

Obesity is a widespread public health problem with profound medical consequences and its burden is increasing worldwide. Obesity causes significant morbidity and mortality and is associated with conditions including cardiovascular disease and diabetes mellitus. Conventional treatment options are insufficient, or in the case of bariatric surgery, quite invasive. The etiology of obesity is complex, but at its core is often a caloric imbalance with an inability to burn off enough calories to exceed caloric intake, resulting in storage. Interventions such as dieting often lead to decreased resting energy expenditure (REE), with a rebound in weight ("yo-yo effect" or weight cycling). Strategies that increase REE are attractive treatment options. Brown fat tissue engages in nonshivering thermogenesis whereby mitochondrial respiration is uncoupled from ATP production, increasing REE. Medications that replicate brown fat metabolism by mitochondrial uncoupling (e.g., 2,4-dinitrophenol) effectively promote weight loss but are limited by toxicity to a narrow therapeutic range. This review explores the possibility of a new therapeutic approach to engineer autologous T cells into acquiring a thermogenic phenotype like brown fat. Engineered autologous T cells have been used successfully for years in the treatment of cancers (chimeric antigen receptor T cells), and the principle of engineering T cells ex vivo and transferring them back to the patient is established. Engineering T cells to acquire a brown fat-like metabolism could increase REE without the risks of pharmacological mitochondrial uncoupling. These thermogenic T cells may increase basal metabolic rate and are therefore a potentially novel therapeutic strategy for obesity.

Keywords: cell engineering; energy expenditure; mitochondrial uncoupling; thermogenesis; weight loss.

Figure 1.

Weight cycling due to low resting energy expenditure. Dieting decreases weight through reduction of energy intake but triggers a reduction in resting energy expenditure (REE), promoting weight cycling.

Figure 2.

Uncoupling protein 1 (UCP1) can enable protons to equilibrate across the inner mitochondrial membrane. The electron transport chain receives electrons from fatty acid oxidation and the Krebs cycle and transports protons across the inner mitochondrial membrane from the mitochondrial matrix into mitochondrial intermembrane space. A proton gradient is formed and can be utilized to phosphorylate ADP to ATP (oxidative phosphorylation). Uncoupling protein-1 (UCP1) is a protonophore that can be expressed in the inner mitochondrial membrane, and may, under certain circumstances, open and allow protons to equilibrate without having to go through ATP synthase. Mutant UCP1 (Gly76Δ or Gly175Δ) is a variant of UCP1 that is always open without regulation.

Figure 3.

Mitochondrial uncoupling and NADH oxidation. Schematic illustrating two proposed ways to engineer autologous T cells to acquire a brown fat energy wasting phenotype. Left: physiological oxidative phosphorylation, generating electrons in the tricarboxylic acid (TCA) cycle, and fatty acid β-oxidation (β-ox), which are loaded on NAD⁺, reducing it to NADH. NADH delivers the electrons to the electron transport chain (ETC) while being reoxidized to NAD⁺ and enabled to pick up new electrons. In the brown adipose tissue (BAT) solution (middle), mutant uncoupling protein-1 is transduced into T cells to make the ETC run futile without producing ATP. In the Lactobacillus brevis NADH oxidase (LbNOX) solution (right), NADH is oxidized by a humanized bacterial enzyme that removes the electrons from NADH before it can deliver them to the electron transport chain. Both solutions create an energy wasting metabolic phenotype.

Figure 4.

Thermogenic T cell engineering therapy. An obese patient with insufficient resting energy expenditure donates autologous CD4⁺ T cells, which are genetically engineered ex vivo to acquire a brown fat energy wasting phenotype. The genetically engineered thermogenic T cells are then transfused back to the patient, with the goal of increasing resting energy expenditure and re-establishing a negative energy balance, and thus aiding in the treatment of obesity.