The Combination of High Levels of Adiponectin and Insulin Resistance Are Affected by Aging in Non-Obese Old Peoples

BackgroundAdipokine dysregulation is a key feature of insulin resistance and a metabolic syndrome associated with obesity. Low adiponectin levels are associated with higher risks of cardiovascular diseases (CVD). However, high adiponectin levels have also been associated with increased all-cause and cardiovascular mortality in the elderly. This adiponectin paradox has yet to be clarified, which has hindered our understanding of the biological role of adiponectin. Adipokine dysregulation and insulin resistance are also associated with energy-deprivation conditions, such as frailty in old age. The objective of this study was to investigate the association between plasma adiponectin and insulin resistance using the homeostasis model assessment for insulin resistance (HOMA-IR) classified by age. In particular, we sought to determine the factors of the subjects associated with both high adiponectin levels and HOMA-IR (H-adiponectin/H-HOMA) and high adiponectin levels and low HOMA-IR (H-adiponectin/L-HOMA).MethodsThe eligible subjects in this cross-sectional study were 33,216 individuals who had undergone health checkups at the Physical Checkup Center of Sumitomo Hospital between April 2008 and December 2018. After excluding 26,371 individuals who were under 60 years old, 529 who had been taking medications for diabetes mellitus, and 690 with missing data, the present study included 5,673 (3,467 males, 2,206 females) subjects with no missing data. The relationship between serum adiponectin levels and HOMA-IR was assessed using logistic regression models adjusted by clinically relevant factors.ResultsIn the multivariable logistic regression analysis, age and low BMI were shown to positively correlate with the characteristics of H-adiponectin/H-HOMA. In females, systolic blood pressure was also shown to be an associated factor.ConclusionIn conclusion, this study showed that aging or a low BMI may contribute to high adiponectin levels and insulin resistance.

In Silico Evaluation of Binding of 2-Deoxy-D-Glucose with Mpro of nCoV to Combat COVID-19

COVID-19 has threatened the existence of humanity andthis infection occurs due to SARS-CoV-2 or novel coronavirus, was first reported in Wuhan, China. Therefore, there is a need to find a promising drug to cure the people suffering from the infection. The second wave of this viral infection was shaking the world in the first half of 2021. Drugs Controllers of India has allowed the emergency use of 2-deoxy-D-glucose (2DG) in 2021 for patients suffering from this viral infection. The potentiality of 2-deoxy-D-glucose to intervene in D-glucose metabolism exists and energy deprivation is an effective parameter to inhibit cancer cell development. Once 2DG arrives in the cells, it becomes phosphorylated to 2-deoxy-D-glucose-6-phosphate (2-DG6P), a charged molecule expressively captured inside the cells. On the other hand, 2DG lacks the ability to convert into fructose-6-phosphate, resulting in a hampering of the activity of both glucose-6-phosphate isomerase and hexokinase, and finally causing cell death. Hence, the potential and effectiveness of 2DG with the main protease (Mpro) of novel coronavirus (nCoV) should be investigated using the molecular docking and molecular dynamics (MD) simulations. The ability of 2DG to inhibit the Mpro of nCoV is compared with 2-deoxyglucose (2DAG), an acyclic molecule, and 2-deoxy-D-ribose (2DR). The binding energy of the molecules with the Mpro of nCoV is calculated using molecular docking and superimposed analysis data is obtained. The binding energy of 2DG, 2DR and 2DAG was −2.40, −2.22 and −2.88 kcal/mol respectively. Although the molecular docking does not provide reliable information, therefore, the binding affinity can be confirmed by molecular dynamics simulations. Various trajectories such as Rg, RMSD, RMSF, and hydrogen bonds are obtained from the molecular dynamics (MD) simulations. 2DG was found to be a better inhibitor than the 2DAG and 2DR based on the results obtained from the MD simulations at 300 K. Furthermore, temperature-dependent MD simulations of the Mpro of nCoV with promising 2DG was performed at 295, 310 and 315 K, and the effective binding with the Mpro of nCoV occurred at 295 K. With the use of DFT calculations, optimized geometry and localization of electron density of the frontier molecular orbitals were calculated.

Whey-Adapted versus Natural Cow’s Milk Formulation: Distinctive Feeding Responses and Post-Ingestive c-Fos Expression in Laboratory Mice

The natural 20:80 whey:casein ratio in cow’s milk (CM) for adults and infants is adjusted to reflect the 60:40 ratio of human milk, but the feeding and metabolic consequences of this adjustment have been understudied. In adult human subjects, the 60:40 CM differently affects glucose metabolism and hormone release than the 20:80 CM. In laboratory animals, whey-adapted goat’s milk is consumed in larger quantities. It is unknown whether whey enhancement of CM would have similar consequences on appetite and whether it would affect feeding-relevant brain regulatory mechanisms. In this set of studies utilizing laboratory mice, we found that the 60:40 CM was consumed more avidly than the 20:80 control formulation by animals motivated to eat by energy deprivation and by palatability (in the absence of hunger) and that this hyperphagia stemmed from prolongation of the meal. Furthermore, in two-bottle choice paradigms, whey-adapted CM was preferred against the natural 20:80 milk. The intake of the whey-adapted CM induced neuronal activation (assessed through analysis of c-Fos expression in neurons) in brain sites promoting satiation, but importantly, this activation was less pronounced than after ingestion of the natural 20:80 whey:casein CM. Activation of hypothalamic neurons synthesizing anorexigenic neuropeptide oxytocin (OT) was also less robust after the 60:40 CM intake than after the 20:80 CM. Pharmacological blockade of the OT receptor in mice led to an increase in the consumption only of the 20:80 CM, thus, of the milk that induced greater activation of OT neurons. We conclude that the whey-adapted CM is overconsumed compared to the natural 20:80 CM and that this overconsumption is associated with weakened responsiveness of central networks involved in satiety signalling, including OT.

Acetyl-CoA production by specific metabolites promotes cardiac repair after myocardial infarction via histone acetylation

Myocardial infarction (MI) is accompanied by severe energy deprivation and extensive epigenetic changes. However, how energy metabolism and chromatin modifications are interlinked during MI and heart repair has been poorly explored. Here, we examined the effect of different carbon sources that are involved in the major metabolic pathways of acetyl-CoA synthesis on myocardial infarction and found that elevation of acetyl-CoA by sodium octanoate (8C) significantly improved heart function in ischemia reperfusion (I/R) rats. Mechanistically, 8C reduced I/R injury by promoting histone acetylation which in turn activated the expression of antioxidant genes and inhibited cardiomyocyte (CM) apoptosis. Furthermore, we elucidated that 8C-promoted histone acetylation and heart repair were carried out by metabolic enzyme medium-chain acyl-CoA dehydrogenase (MCAD) and histone acetyltransferase Kat2a, suggesting that 8C dramatically improves cardiac function mainly through metabolic acetyl-CoA-mediated histone acetylation. Therefore, our study uncovers an interlinked metabolic/epigenetic network comprising 8C, acetyl-CoA, MCAD, and Kat2a to combat heart injury.

New Insights Into the Role of Mitochondria Quality Control in Ischemic Heart Disease

IHD is a significant cause of mortality and morbidity worldwide. In the acute phase, it's demonstrated as myocardial infarction and ischemia-reperfusion injury, while in the chronic stage, the ischemic heart is mainly characterised by adverse myocardial remodelling. Although interventions such as thrombolysis and percutaneous coronary intervention could reduce the death risk of these patients, the underlying cellular and molecular mechanisms need more exploration. Mitochondria are crucial to maintain the physiological function of the heart. During IHD, mitochondrial dysfunction results in the pathogenesis of ischemic heart disease. Ischemia drives mitochondrial damage not only due to energy deprivation, but also to other aspects such as mitochondrial dynamics, mitochondria-related inflammation, etc. Given the critical roles of mitochondrial quality control in the pathological process of ischemic heart disease, in this review, we will summarise the efforts in targeting mitochondria (such as mitophagy, mtROS, and mitochondria-related inflammation) on IHD. In addition, we will briefly revisit the emerging therapeutic targets in this field.

AMPK promotes Arf6 activation in a kinase-independent manner upon energy deprivation

AMP-activated protein kinase (AMPK) is a crucial cellular nutrient and energy sensor that maintains energy homeostasis. AMPK also governs cancer cell invasion and migration by regulating gene expression and activating multiple cellular signaling pathways. ADP-ribosylation factor 6 (Arf6) can be activated via nucleotide exchange by guanine nucleotide exchange factors (GEFs), and its activation also regulates tumor invasion and migration. By studying GEF-mediated Arf6 activation, we elucidated that AMPK functions as a noncanonical GEF for Arf6 in a kinase-independent manner. Moreover, by examining the physiological role of the AMPK-Arf6 axis, we determined that AMPK activates Arf6 upon glucose starvation and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) treatment. We further identified the binding motif in the C-terminal regulatory domain of AMPK that is responsible for promoting Arf6 activation and thus inducing cell migration and invasion. These findings reveal a noncanonical role of AMPK in which its C-terminal regulatory domain serves as a GEF for Arf6 during energy deprivation.

Starvation to Glucose Reprograms Development of Neurovascular Unit in Embryonic Retinal Cells

Perinatal exposure to starvation is a risk factor for development of severe retinopathy in adult patients with diabetes. However, the underlying mechanisms are not completely understood. In the present study, we shed light on molecular consequences of exposure to short-time glucose starvation on the transcriptome profile of mouse embryonic retinal cells. We found a profound downregulation of genes regulating development of retinal neurons, which was accompanied by reduced expression of genes encoding for glycolytic enzymes and glutamatergic signaling. At the same time, glial and vascular markers were upregulated, mimicking the diabetes-associated increase of angiogenesis—a hallmark of pathogenic features in diabetic retinopathy. Energy deprivation as a consequence of starvation to glucose seems to be compensated by upregulation of genes involved in fatty acid elongation. Results from the present study demonstrate that short-term glucose deprivation during early fetal life differentially alters expression of metabolism- and function-related genes and could have detrimental and lasting effects on gene expression in the retinal neurons, glial cells, and vascular elements and thus potentially disrupting gene regulatory networks essential for the formation of the retinal neurovascular unit. Abnormal developmental programming during retinogenesis may serve as a trigger of reactive gliosis, accelerated neurodegeneration, and increased vascularization, which may promote development of severe retinopathy in patients with diabetes later in life.

Ketogenic diet: A promising neuroprotective composition for managing Alzheimer’s diseases and its pathological mechanisms

: Ketogenic diet and ketone bodies gained significant attention in recent years due to their ability to influence the specific energy metabolism and restoration of mitochondrial homeostasis that can help in hindering the progression of many metabolic diseases including diabetes and neurodegenerative diseases. Ketogenic diet consists of high fat and low carbohydrate contents which makes the body glucose deprived and rely on alternative sources (ketone bodies) for energy. It has been initially designed and supplemented for the treatment of epilepsy and later its influence on many energy-deriving biochemical pathways made it a highly sorted food supplement for many metabolic diseases and even by healthy individuals for body building and calorie restriction. Among the reported therapeutic action over a range of diseases, neurodegenerative disorders especially Alzheimer’s disease gained the attention of many researchers and clinicians because of its potency and its easier supplementation as a food additive. Complex pathology and multiple influencing factors of Alzheimer’s disease make exploration of its therapeutic strategies a demanding task. It was a common phenomenon that energy deprivation in neurological disorders including Alzheimer’s disease, to progress rapidly. The ability of ketone bodies to stabilize the mitochondrial energy metabolism makes it a suitable intervening agent. In this review, we will discuss various research progress made with regards to ketone bodies/ketogenic diet for management of Alzheimer’s disease and elaborate in detail about the mechanisms that are influenced during their therapeutic action.

Assessing Energy Poverty in Urban Regions of Mexico: The Role of Thermal Comfort and Bioclimatic Context

The increase of energy access to households has been a global priority. By 2018, 89.59% of the world population had access to electricity, while 97.26% of the persons living in urban areas (The Mexican Government reports it at 99.99%) had access. We must now move beyond access to electricity and address energy poverty in urban spaces. A household is energy poor when their inhabitants are incapable of securing proper domestic energy services. Several different methodologies were developed to measure energy poverty. The Multidimensional Energy Poverty Index (MEPI) by Nussbaumer has been successfully used in Africa and in Latin-America. The MEPI considers five dimensions: cooking, lighting, household appliances, entertainment/education and communication. We developed a Multidimensional Energy Deprivation Index (MEDI), based on MEPI. Thermal comfort has been included as sixth dimension, by considering the temperature of the region where the household is located. We found important differences between MEPI and MEDI for Mexico at the national level (urban-MEPI at 0.028 vs. 0.071 urban-MEDI, which implies a higher degree of energy poverty). Also, differences between geopolitical and bioclimatic regions were found. Having better ways to assess energy poverty in the urban context is a key factor to develop effective public policies that might alleviate it.

Glial Chloride Homeostasis Under Transient Ischemic Stress

High water permeabilities permit rapid adjustments of glial volume upon changes in external and internal osmolarity, and pathologically altered intracellular chloride concentrations ([Cl–]int) and glial cell swelling are often assumed to represent early events in ischemia, infections, or traumatic brain injury. Experimental data for glial [Cl–]int are lacking for most brain regions, under normal as well as under pathological conditions. We measured [Cl–]int in hippocampal and neocortical astrocytes and in hippocampal radial glia-like (RGL) cells in acute murine brain slices using fluorescence lifetime imaging microscopy with the chloride-sensitive dye MQAE at room temperature. We observed substantial heterogeneity in baseline [Cl–]int, ranging from 14.0 ± 2.0 mM in neocortical astrocytes to 28.4 ± 3.0 mM in dentate gyrus astrocytes. Chloride accumulation by the Na+-K+-2Cl– cotransporter (NKCC1) and chloride outward transport (efflux) through K+-Cl– cotransporters (KCC1 and KCC3) or excitatory amino acid transporter (EAAT) anion channels control [Cl–]int to variable extent in distinct brain regions. In hippocampal astrocytes, blocking NKCC1 decreased [Cl–]int, whereas KCC or EAAT anion channel inhibition had little effect. In contrast, neocortical astrocytic or RGL [Cl–]int was very sensitive to block of chloride outward transport, but not to NKCC1 inhibition. Mathematical modeling demonstrated that higher numbers of NKCC1 and KCC transporters can account for lower [Cl–]int in neocortical than in hippocampal astrocytes. Energy depletion mimicking ischemia for up to 10 min did not result in pronounced changes in [Cl–]int in any of the tested glial cell types. However, [Cl–]int changes occurred under ischemic conditions after blocking selected anion transporters. We conclude that stimulated chloride accumulation and chloride efflux compensate for each other and prevent glial swelling under transient energy deprivation.