The Role of Mitochondrial Adaptation and Metabolic Flexibility in the Pathophysiology of Obesity and Insulin Resistance: an Updated Overview

Tsilingiris, Dimitrios; Tzeravini, Evangelia; Koliaki, Chrysi; Kokkinos, Alexander

doi:10.1007/s13679-021-00434-0

Cited by 23 publications

(17 citation statements)

References 163 publications

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“…In agreement, previous evidence showed that men with high insulin sensitivity (vs. low) better coupled fat oxidation to elevated plasma non-esterified fatty acids (NEFA) concentration, and they also had lower (borderline) intramyocellular lipid content ( 13 ). Even so, evidence regarding the causality between MetF and metabolic health remains inconclusive, as has been extensively discussed elsewhere ( 8 , 14 ). On the one hand, MetF has been assessed by different methods, thus dampening comparability among studies ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

Similar Metabolic Health in Overweight/Obese Individuals With Contrasting Metabolic Flexibility to an Oral Glucose Tolerance Test

et al. 2021

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Background: Low metabolic flexibility (MetF) may be an underlying factor for metabolic health impairment. Individuals with low MetF are thus expected to have worse metabolic health than subjects with high MetF. Therefore, we aimed to compare metabolic health in individuals with contrasting MetF to an oral glucose tolerance test (OGTT).Methods: In individuals with excess body weight, we measured MetF as the change in respiratory quotient (RQ) from fasting to 1 h after ingestion of a 75-g glucose load (i.e., OGTT). Individuals were then grouped into low and high MetF (Low-MetF n = 12; High-MetF n = 13). The groups had similar body mass index, body fat, sex, age, and maximum oxygen uptake. Metabolic health markers (clinical markers, insulin sensitivity/resistance, abdominal fat, and intrahepatic fat) were compared between groups.Results: Fasting glucose, triglycerides (TG), and high-density lipoprotein (HDL) were similar between groups. So were insulin sensitivity/resistance, visceral, and intrahepatic fat. Nevertheless, High-MetF individuals had higher diastolic blood pressure, a larger drop in TG concentration during the OGTT, and a borderline significant (P = 0.05) higher Subcutaneous Adipose Tissue (SAT). Further, compared to Low-MetF, High-MetF individuals had an about 2-fold steeper slope for the relationship between SAT and fat mass index.Conclusion: Individuals with contrasting MetF to an OGTT had similar metabolic health. Yet High-MetF appears related to enhanced circulating TG clearance and enlarged subcutaneous fat.

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Section: Introductionmentioning

confidence: 99%

Similar Metabolic Health in Overweight/Obese Individuals With Contrasting Metabolic Flexibility to an Oral Glucose Tolerance Test

et al. 2021

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“…A limitation of our review process was that we only searched in PubMed, thus probably missing evidence from other databases. Note, however, that PubMed has been long recognized as an optimal tool for biomedical electronic research (52), and the most influential research on MetF is indexed therein [see (9,(41)(42)(43)(44)53) and their references]. Another limitation is that we focused only on reports in adult humans, thus excluding children, adolescents, and older adults, in whom several insightful studies have been conducted [see for example: (54)(55)(56)(57)].…”

Section: Discussionmentioning

confidence: 99%

“…Our review also has some strengths worth mentioning. First, although several narrative reviews about MetF have been published (9,(41)(42)(43)(44)53), as far as we know, this is the first systematic review regarding MetF. Second, we only considered reports with moderate-to-high methodological quality to draw our conclusions; yet we presented the data for the reports with lower methodological quality as well (Supplementary Table 3).…”

Section: Discussionmentioning

confidence: 99%

Association Between Adipose Tissue Characteristics and Metabolic Flexibility in Humans: A Systematic Review

et al. 2021

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Adipose tissue total amount, distribution, and phenotype influence metabolic health. This may be partially mediated by the metabolic effects that these adipose tissue characteristics exert on the nearby and distant tissues. Thus, adipose tissue may influence the capacity of cells, tissues, and the organism to adapt fuel oxidation to fuel availability, i.e., their metabolic flexibility (MetF). Our aim was to systematically review the evidence for an association between adipose tissue characteristics and MetF in response to metabolic challenges in human adults. We searched in PubMed (last search on September 4, 2021) for reports that measured adipose tissue characteristics (total amount, distribution, and phenotype) and MetF in response to metabolic challenges (as a change in respiratory quotient) in humans aged 18 to <65 years. Any study design was considered, and the risk of bias was assessed with a checklist for randomized and non-randomized studies. From 880 records identified, 22 remained for the analysis, 10 of them measured MetF in response to glucose plus insulin stimulation, nine in response to dietary challenges, and four in response to other challenges. Our main findings were that: (a) MetF to glucose plus insulin stimulation seems inversely associated with adipose tissue total amount, waist circumference, and visceral adipose tissue; and (b) MetF to dietary challenges does not seem associated with adipose tissue total amount or distribution. In conclusion, evidence suggests that adipose tissue may directly or indirectly influence MetF to glucose plus insulin stimulation, an effect probably explained by skeletal muscle insulin sensitivity.Systematic Review Registration: PROSPERO [CRD42020167810].

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“…We propose that mitochondrial inflexibility is a mitochondrial compensatory response to fuel surplus, where signaling pathways are involved in the suppression of AMPK and Sirtuin-1 (SIRT1) and the activation of mammalian target of rapamycin (mTOR). This mitochondrial dysfunction worsens metabolic disorders by reducing energy expenditure, which leads to further accumulation of fuels in the insulin-sensitive cells (49). These mitochondrial dysfunctions are improved by lifestyle modifications such as physical exercise, calorie restriction, and weight loss, which are established strategies in the control of obesity, type 2 diabetes, and metabolic disorders (27).…”

Section: Energy Surplus Leads To Mitochondrial Dysfunction In Obesitymentioning

confidence: 99%

Mitochondria in Sex Hormone-Induced Disorder of Energy Metabolism in Males and Females

et al. 2021

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Androgens have a complex role in the regulation of insulin sensitivity in the pathogenesis of type 2 diabetes. In male subjects, a reduction in androgens increases the risk for insulin resistance, which is improved by androgen injections. However, in female subjects with polycystic ovary syndrome (PCOS), androgen excess becomes a risk factor for insulin resistance. The exact mechanism underlying the complex activities of androgens remains unknown. In this review, a hormone synergy-based view is proposed for understanding this complexity. Mitochondrial overactivation by substrate influx is a mechanism of insulin resistance in obesity. This concept may apply to the androgen-induced insulin resistance in PCOS. Androgens and estrogens both exhibit activities in the induction of mitochondrial oxidative phosphorylation. The two hormones may synergize in mitochondria to induce overproduction of ATP. ATP surplus in the pancreatic β-cells and α-cells causes excess secretion of insulin and glucagon, respectively, leading to peripheral insulin resistance in the early phase of type 2 diabetes. In the skeletal muscle and liver, the ATP surplus contributes to insulin resistance through suppression of AMPK and activation of mTOR. Consistent ATP surplus leads to mitochondrial dysfunction as a consequence of mitophagy inhibition, which provides a potential mechanism for mitochondrial dysfunction in β-cells and brown adipocytes in PCOS. The hormone synergy-based view provides a basis for the overactivation and dysfunction of mitochondria in PCOS-associated type 2 diabetes. The molecular mechanism for the synergy is discussed in this review with a focus on transcriptional regulation. This view suggests a unifying mechanism for the distinct metabolic roles of androgens in the control of insulin action in men with hypogonadism and women with PCOS.

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The Role of Mitochondrial Adaptation and Metabolic Flexibility in the Pathophysiology of Obesity and Insulin Resistance: an Updated Overview

Cited by 23 publications

References 163 publications

Similar Metabolic Health in Overweight/Obese Individuals With Contrasting Metabolic Flexibility to an Oral Glucose Tolerance Test

Similar Metabolic Health in Overweight/Obese Individuals With Contrasting Metabolic Flexibility to an Oral Glucose Tolerance Test

Association Between Adipose Tissue Characteristics and Metabolic Flexibility in Humans: A Systematic Review

Mitochondria in Sex Hormone-Induced Disorder of Energy Metabolism in Males and Females

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