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      Ketones Elicit Distinct Alterations in Adipose Mitochondrial Bioenergetics

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          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.

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          Most cited references25

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          Prevalence of Obesity and Severe Obesity Among Adults: United States, 2017-2018.

          Obesity is associated with serious health risks (1). Severe obesity further increases the risk of obesity-related complications, such as coronary heart disease and end-stage renal disease (2,3). From 1999-2000 through 2015-2016, a significantly increasing trend in obesity was observed (4). This report provides the most recent national data for 2017-2018 on obesity and severe obesity prevalence among adults by sex, age, and race and Hispanic origin. Trends from 1999-2000 through 2017-2018 for adults aged 20 and over are also presented.
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            A high-fat, ketogenic diet induces a unique metabolic state in mice.

            Ketogenic diets have been used as an approach to weight loss on the basis of the theoretical advantage of a low-carbohydrate, high-fat diet. To evaluate the physiological and metabolic effects of such diets on weight we studied mice consuming a very-low-carbohydrate, ketogenic diet (KD). This diet had profound effects on energy balance and gene expression. C57BL/6 mice animals were fed one of four diets: KD; a commonly used obesogenic high-fat, high-sucrose diet (HF); 66% caloric restriction (CR); and control chow (C). Mice on KD ate the same calories as mice on C and HF, but weight dropped and stabilized at 85% initial weight, similar to CR. This was consistent with increased energy expenditure seen in animals fed KD vs. those on C and CR. Microarray analysis of liver showed a unique pattern of gene expression in KD, with increased expression of genes in fatty acid oxidation pathways and reduction in lipid synthesis pathways. Animals made obese on HF and transitioned to KD lost all excess body weight, improved glucose tolerance, and increased energy expenditure. Analysis of key genes showed similar changes as those seen in lean animals placed directly on KD. Additionally, AMP kinase activity was increased, with a corresponding decrease in ACC activity. These data indicate that KD induces a unique metabolic state congruous with weight loss.
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              Brown Adipose Tissue in Morbidly Obese Subjects

              Background Cold-stimulated adaptive thermogenesis in brown adipose tissue (BAT) to increase energy expenditure is suggested as a possible therapeutic target for the treatment of obesity. We have recently shown high prevalence of BAT in adult humans, which was inversely related to body mass index (BMI) and body fat percentage (BF%), suggesting that obesity is associated with lower BAT activity. Here, we examined BAT activity in morbidly obese subjects and its role in cold-induced thermogenesis (CIT) after applying a personalized cooling protocol. We hypothesize that morbidly obese subjects show reduced BAT activity upon cold exposure. Methods and Findings After applying a personalized cooling protocol for maximal non-shivering conditions, BAT activity was determined using positron-emission tomography and computed tomography (PET-CT). Cold-induced BAT activity was detected in three out of 15 morbidly obese subjects. Combined with results from lean to morbidly obese subjects (n = 39) from previous study, the collective data show a highly significant correlation between BAT activity and body composition (P<0.001), respectively explaining 64% and 60% of the variance in BMI (r = 0.8; P<0.001) and BF% (r = 0.75; P<0.001). Obese individuals demonstrate a blunted CIT combined with low BAT activity. Only in BAT-positive subjects (n = 26) mean energy expenditure was increased significantly upon cold exposure (51.5±6.7 J/s versus 44.0±5.1 J/s, P = 0.001), and the increase was significantly higher compared to BAT-negative subjects (+15.5±8.9% versus +3.6±8.9%, P = 0.001), indicating a role for BAT in CIT in humans. Conclusions This study shows that in an extremely large range of body compositions, BAT activity is highly correlated with BMI and BF%. BAT-positive subjects showed higher CIT, indicating that BAT is also in humans involved in adaptive thermogenesis. Increasing BAT activity could be a therapeutic target in (morbid) obesity.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                29 August 2020
                September 2020
                : 21
                : 17
                : 6255
                Affiliations
                [1 ]Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA; chase.m.walton@ 123456gmail.com (C.M.W.); sam.jacobsen@ 123456icloud.com (S.M.J.); bdallon@ 123456gmail.com (B.W.D.); ersaito3@ 123456gmail.com (E.R.S.); lenaehouse@ 123456gmail.com (S.L.H.B.); david_thomson@ 123456byu.edu (D.M.T.)
                [2 ]Department of Exercise Sciences, Brigham Young University, Provo, UT 84602, USA; lance.davidson@ 123456byu.edu (L.E.D.); robhyldahl@ 123456byu.edu (R.D.H.)
                Author notes
                [* ]Correspondence: bikman@ 123456byu.edu ; Tel.: +1-801-422-1798
                Author information
                https://orcid.org/0000-0002-1383-0666
                Article
                ijms-21-06255
                10.3390/ijms21176255
                7503338
                32872407
                c45ec6b1-7d46-4b7b-9008-8e28a1f49c49
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 06 August 2020
                : 27 August 2020
                Categories
                Article

                Molecular biology
                mitochondria,uncoupling,ketones,adipocyte
                Molecular biology
                mitochondria, uncoupling, ketones, adipocyte

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