bims-mimeim 2021-04-11 papers

Issue of 2021–04–11
four papers selected by
Matthew C. Sinton, University of Glasgow

Front Endocrinol (Lausanne). 2021 ;12 635175

Sphingolipids as a Culprit of Mitochondrial Dysfunction in Insulin Resistance and Type 2 Diabetes.

Kamila Roszczyc-Owsiejczuk, Piotr Zabielski.

Insulin resistance is defined as a complex pathological condition of abnormal cellular and metabolic response to insulin. Obesity and consumption of high-fat diet lead to ectopic accumulation of bioactive lipids in insulin-sensitive tissues. Intracellular lipid accumulation is regarded as one of the major factors in the induction of insulin resistance and type 2 diabetes (T2D). A significant number of studies have described the involvement of ceramides and other sphingolipids in the inhibition of insulin-signaling pathway in both skeletal muscles and the liver. Adverse effects of sphingolipid accumulation have recently been linked to the activation of protein kinase Cζ (PKCζ) and protein phosphatase 2A (PP2A), which, in turn, negatively affect phosphorylation of serine/threonine kinase Akt [also known as protein kinase B (PKB)], leading to decreased glucose uptake in skeletal muscles as well as increased gluconeogenesis and glycogenolysis in the liver. Sphingolipids, in addition to their direct impact on the insulin signaling pathway, may be responsible for other negative aspects of diabetes, namely mitochondrial dysfunction and deficiency. Mitochondrial health, which is characterized by appropriate mitochondrial quantity, oxidative capacity, controlled oxidative stress, undisturbed respiratory chain function, adenosine triphosphate (ATP) production and mitochondrial proliferation through fission and fusion, is impaired in the skeletal muscles and liver of T2D subjects. Recent findings suggest that impaired mitochondrial function may play a key role in the development of insulin resistance. Mitochondria stay in contact with the endoplasmic reticulum (ER), Golgi membranes and mitochondria-associated membranes (MAM) that are the main places of sphingolipid synthesis. Moreover, mitochondria are capable of synthesizing ceramide though ceramide synthase (CerS) activity. Recently, ceramides have been demonstrated to negatively affect mitochondrial respiratory chain function and fission/fusion activity, which is also a hallmark of T2D. Despite a significant correlation between sphingolipids, mitochondrial dysfunction, insulin resistance and T2D, this subject has not received much attention compared to the direct effect of sphingolipids on the insulin signaling pathway. In this review, we focus on the current state of scientific knowledge regarding the involvement of sphingolipids in the induction of insulin resistance by inhibiting mitochondrial function.

Keywords: ceramide; insulin resistance; metabolism; mitochondrial dysfunction; sphingolipids; type 2 diabetes

DOI: https://doi.org/10.3389/fendo.2021.635175

Proc Natl Acad Sci U S A. 2021 Mar 16. pii: e2021073118. [Epub ahead of print]118(11):

DNMT1 maintains metabolic fitness of adipocytes through acting as an epigenetic safeguard of mitochondrial dynamics.

Yoon Jeong Park, Sangseon Lee, Sangsoo Lim, Hahn Nahmgoong, Yul Ji, Jin Young Huh, Assim A Alfadda, Sun Kim, Jae Bum Kim.

White adipose tissue (WAT) is a key regulator of systemic energy metabolism, and impaired WAT plasticity characterized by enlargement of preexisting adipocytes associates with WAT dysfunction, obesity, and metabolic complications. However, the mechanisms that retain proper adipose tissue plasticity required for metabolic fitness are unclear. Here, we comprehensively showed that adipocyte-specific DNA methylation, manifested in enhancers and CTCF sites, directs distal enhancer-mediated transcriptomic features required to conserve metabolic functions of white adipocytes. Particularly, genetic ablation of adipocyte Dnmt1, the major methylation writer, led to increased adiposity characterized by increased adipocyte hypertrophy along with reduced expansion of adipocyte precursors (APs). These effects of Dnmt1 deficiency provoked systemic hyperlipidemia and impaired energy metabolism both in lean and obese mice. Mechanistically, Dnmt1 deficiency abrogated mitochondrial bioenergetics by inhibiting mitochondrial fission and promoted aberrant lipid metabolism in adipocytes, rendering adipocyte hypertrophy and WAT dysfunction. Dnmt1-dependent DNA methylation prevented aberrant CTCF binding and, in turn, sustained the proper chromosome architecture to permit interactions between enhancer and dynamin-1-like protein gene Dnm1l (Drp1) in adipocytes. Also, adipose DNMT1 expression inversely correlated with adiposity and markers of metabolic health but positively correlated with AP-specific markers in obese human subjects. Thus, these findings support strategies utilizing Dnmt1 action on mitochondrial bioenergetics in adipocytes to combat obesity and related metabolic pathology.

Keywords: DNA methylation; adiposity; chromosome structure; metabolic disease; mitochondria

DOI: https://doi.org/10.1073/pnas.2021073118

Elife. 2021 Apr 07. pii: e62591. [Epub ahead of print]10

Glucose restriction drives spatial reorganization of mevalonate metabolism.

Sean M Rogers, Hanaa Hariri, N Ezgi M Wood, Natalie Ortiz Speer, W Mike Henne.

Eukaryotes compartmentalize metabolic pathways into sub-cellular domains, but the role of inter-organelle contacts in organizing metabolic reactions remains poorly understood. Here, we show that in response to acute glucose restriction (AGR) yeast undergo metabolic remodeling of their mevalonate pathway that is spatially coordinated at nucleus-vacuole junctions (NVJs). The NVJ serves as a metabolic platform by selectively retaining HMG-CoA Reductases (HMGCRs), driving mevalonate pathway flux in an Upc2-dependent manner. Both spatial retention of HMGCRs and increased mevalonate pathway flux during AGR is dependent on NVJ tether Nvj1. Furthermore, we demonstrate that HMGCRs associate into high molecular weight assemblies during AGR in an Nvj1-dependent manner. Loss of Nvj1-mediated HMGCR partitioning can be bypassed by artificially multimerizing HMGCRs, indicating NVJ compartmentalization enhances mevalonate pathway flux by promoting the association of HMGCRs in high molecular weight assemblies. Loss of HMGCR compartmentalization perturbs yeast growth following glucose starvation, indicating it promotes adaptive metabolic remodeling. Collectively we propose a non-canonical mechanism regulating mevalonate metabolism via the spatial compartmentalization of rate-limiting HMGCR enzymes at an inter-organelle contact site.

Keywords: S. cerevisiae; cell biology

DOI: https://doi.org/10.7554/eLife.62591

Cell Rep. 2021 Apr 06. pii: S2211-1247(21)00249-7. [Epub ahead of print]35(1): 108935

FoxO1 inhibition alleviates type 2 diabetes-related diastolic dysfunction by increasing myocardial pyruvate dehydrogenase activity.

Keshav Gopal, Rami Al Batran, Tariq R Altamimi, Amanda A Greenwell, Christina T Saed, Seyed Amirhossein Tabatabaei Dakhili, M Toni E Dimaano, Yongneng Zhang, Farah Eaton, Gopinath Sutendra, John R Ussher.

Type 2 diabetes (T2D) increases the risk for diabetic cardiomyopathy and is characterized by diastolic dysfunction. Myocardial forkhead box O1 (FoxO1) activity is enhanced in T2D and upregulates pyruvate dehydrogenase (PDH) kinase 4 expression, which inhibits PDH activity, the rate-limiting enzyme of glucose oxidation. Because low glucose oxidation promotes cardiac inefficiency, we hypothesize that FoxO1 inhibition mitigates diabetic cardiomyopathy by stimulating PDH activity. Tissue Doppler echocardiography demonstrates improved diastolic function, whereas myocardial PDH activity is increased in cardiac-specific FoxO1-deficient mice subjected to experimental T2D. Pharmacological inhibition of FoxO1 with AS1842856 increases glucose oxidation rates in isolated hearts from diabetic C57BL/6J mice while improving diastolic function. However, AS1842856 treatment fails to improve diastolic function in diabetic mice with a cardiac-specific FoxO1 or PDH deficiency. Our work defines a fundamental mechanism by which FoxO1 inhibition improves diastolic dysfunction, suggesting that it may be an approach to alleviate diabetic cardiomyopathy.

Keywords: FoxO1; diabetic cardiomyopathy; diastolic dysfunction; glucose oxidation; pyruvate dehydrogenase; type 2 diabetes

DOI: https://doi.org/10.1016/j.celrep.2021.108935