Ketones Elicit Distinct Alterations in Adipose Mitochondrial Bioenergetics

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.

Mitochondrial Lipid Signaling and Adaptive Thermogenesis

“…A loss of ketone production by the knockout of 3-Hydroxybutyrate Dehydrogenase 1 (Bdh1) led to increased fibrosis and decreased beige adipocyte differentiation in response to cold acclimatization [56]. These findings may explain previous observations that ketogenic-diet-fed mice had increased mitochondrial proteins, UCP1, oxygen consumption, and improved thermoregulation [57,58]. There are also several studies that demonstrate that circulating ketones are elevated in response to cold exposure, including a human study that placed males in a 0 • C room for 90 min.…”

The Ketogenic Diet: Is It an Answer for Sarcopenic Obesity?

“…Ketone bodies are used to replace glucose as a source of energy in most tissues throughout time. Similar to extended fasting, subcutaneous adipose cells re-release fatty acids from depots, which are partially beta-oxidized to produce ketone bodies [ 21 ]. KD appears to increase survival by modulating mammalian target of rapamycin (mTOR), as evidenced by multiple studies in rats.…”

Role of nutritional ketosis in the improvement of metabolic parameters following bariatric surgery

“…At the time of KB assessment, WL was similar between patients with or without ketosis. However, it is tempting to speculate that exposure to mild ketosis led to an improvement of mitochondrial bioenergetics and metabolic health[ 3 , 26 , 27 ], which in turn resulted in improved subsequent WL. Despite having significantly higher LDL cholesterol prior to surgery, patients who developed nutritional ketosis exhibited a numerically greater reduction in LDL at 6 mo as compared with patients who did not develop nutritional ketosis (Figure 2 ).…”