Abstract
Objective: The rampant growth of obesity worldwide has stimulated explosive research into human metabolism. Energy expenditure has been shown to be altered by diets differing in macronutrient composition, with low-carbohydrate, ketogenic diets eliciting a significant increase over other interventions. The central aim of this study was to explore the effects of the ketone β-hydroxybutyrate (βHB) on mitochondrial bioenergetics in adipose tissue. Methods: We employed three distinct systems—namely, cell, rodent, and human models. Following exposure to elevated βHB, we obtained adipose tissue to quantify mitochondrial function. Results: In every model, βHB robustly increased mitochondrial respiration, including an increase of roughly 91% in cultured adipocytes, 113% in rodent subcutaneous adipose tissue (SAT), and 128% in human SAT. However, this occurred without a commensurate increase in adipose ATP production. Furthermore, in cultured adipocytes and rodent adipose, we quantified and observed an increase in the gene expression involved in mitochondrial biogenesis and uncoupling status following βHB exposure. Conclusions: In conclusion, βHB increases mitochondrial respiration, but not ATP production, in mammalian adipocytes, indicating altered mitochondrial coupling. These findings may partly explain the increased metabolic rate evident in states of elevated ketones, and may facilitate the development of novel anti-obesity interventions.
Highlights
In the United States and beyond, obesity has reached a remarkable prevalence
Obesity is typified by excess white adipose tissue (WAT) accumulation, which poses a meaningful risk for developing insulin resistance and type 2 diabetes mellitus [3,4], cardiovascular disease [5], and some cancers [6]
The analysis of mitochondrial respiration indicated an increased rate of oxygen use, we found that βHB had no significant effect on the ATP production in cultured adipocytes (Figure 1C)
Summary
In the United States and beyond, obesity has reached a remarkable prevalence. A total of 42% of US adults are obese [1], and an estimated 88% of adults are considered metabolically unhealthy [2]. The explosion in obesity, and our ongoing failure to broadly address it, has given rise to intensive efforts to better understand adipose tissue physiology. These efforts have revealed, among other things, that humans store fat in two distinct depots that differ by function: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT acts primarily for lipid storage, centralized in unilocular lipid droplets within adipocytes that are catabolized and released as fatty acids when necessary. BAT has a limited lipid storage, with multi-locular lipid droplets co-mingled with a substantial population of mitochondria (giving rise to the distinct reddish-brown color). The mitochondria in WAT are very tightly coupled, which is evidence of a more efficient energy storage profile [9]
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