Targeting Molecular Mechanisms of Obesity- and Type 2 Diabetes Mellitus-Induced Skeletal Muscle Atrophy with Nerve Growth Factor.

Skeletal muscle plays a critical role in metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM). Muscle atrophy, characterized by a decrease in muscle mass and function, occurs due to an imbalance between the rates of muscle protein synthesis and degradation. This study aimed to investigate the molecular mechanisms that lead to muscle atrophy in obese and T2DM mouse models. Additionally, the effect of nerve growth factor (NGF) on the protein synthesis and degradation pathways was examined. Male mice were divided into three groups: a control group that was fed a standard chow diet, and two experimental groups that were fed a Western diet. After 8 weeks, the diabetic group was injected with streptozotocin to induce T2DM. Each group was then further divided into NGF-treated or non-treated control group. In the gastrocnemius muscles of the Western diet group, increased expressions of myostatin, autophagy markers, and ubiquitin ligases were observed. Skeletal muscle tissue morphology indicated signs of muscle atrophy in both obese and diabetic mice. The NGF-treated group showed a prominent decrease in the protein levels of myostatin and autophagy markers. Furthermore, the NGF-treated group showed an increased Cyclin D1 level. Western diet-induced obesity and T2DM may be linked to muscle atrophy through upregulation of myostatin and subsequent increase in the ubiquitin and autophagy systems. Moreover, NGF treatment may improve muscle protein synthesis and cell cycling.

Prevalence and Mechanisms of Skeletal Muscle Atrophy in Metabolic Conditions.

Skeletal muscle atrophy is prevalent in a myriad of pathological conditions, such as diabetes, denervation, long-term immobility, malnutrition, sarcopenia, obesity, Alzheimer's disease, and cachexia. This is a critically important topic that has significance in the health of the current society, particularly older adults. The most damaging effect of muscle atrophy is the decreased quality of life from functional disability, increased risk of fractures, decreased basal metabolic rate, and reduced bone mineral density. Most skeletal muscle in humans contains slow oxidative, fast oxidative, and fast glycolytic muscle fiber types. Depending on the pathological condition, either oxidative or glycolytic muscle type may be affected to a greater extent. This review article discusses the prevalence of skeletal muscle atrophy and several mechanisms, with an emphasis on high-fat, high-sugar diet patterns, obesity, and diabetes, but including other conditions such as sarcopenia, Alzheimer's disease, cancer cachexia, and heart failure.

The Effects of Momordica charantia on Type 2 Diabetes Mellitus and Alzheimer's Disease.

T2DM is a complex metabolic disorder characterized by hyperglycemia and glucose intolerance. It is recognized as one of the most common metabolic disorders and its prevalence continues to raise major concerns in healthcare globally. Alzheimer's disease (AD) is a gradual neurodegenerative brain disorder characterized by the chronic loss of cognitive and behavioral function. Recent research suggests a link between the two diseases. Considering the shared characteristics of both diseases, common therapeutic and preventive agents are effective. Certain bioactive compounds such as polyphenols, vitamins, and minerals found in vegetables and fruits can have antioxidant and anti-inflammatory effects that allow for preventative or potential treatment options for T2DM and AD. Recently, it has been estimated that up to one-third of patients with diabetes use some form of complementary and alternative medicine. Increasing evidence from cell or animal models suggests that bioactive compounds may have a direct effect on reducing hyperglycemia, amplifying insulin secretion, and blocking the formation of amyloid plaques. One plant that has received substantial recognition for its numerous bioactive properties is Momordica charantia (M. charantia), otherwise known as bitter melon, bitter gourd, karela, and balsam pear. M. charantia is utilized for its glucose-lowering effects and is often used as a treatment for diabetes and related metabolic conditions amongst the indigenous populations of Asia, South America, India, and East Africa. Several pre-clinical studies have documented the beneficial effects of M. charantia through various postulated mechanisms. Throughout this review, the underlying molecular mechanisms of the bioactive components of M. charantia will be highlighted. More studies will be necessary to establish the clinical efficacy of the bioactive compounds within M. charantia to effectively determine its pertinence in the treatment of metabolic disorders and neurodegenerative diseases, such as T2DM and AD.

Influence of Race and High Laminar Shear Stress on TNFR1 Signaling in Endothelial Cells.

Tumor necrosis factor (TNF) binding to endothelial TNF receptor-I (TNFR-I) facilitates monocyte recruitment and chronic inflammation, leading to the development of atherosclerosis. In vitro data show a heightened inflammatory response and atherogenic potential in endothelial cells (ECs) from African American (AA) donors. High laminar shear stress (HSS) can mitigate some aspects of racial differences in endothelial function at the cellular level. We examined possible racial differences in TNF-induced monocyte adhesion and TNFR1 signaling complex expression/activity, along with the effects of HSS. Tohoku Hospital Pediatrics-1 (THP-1) monocytes were used in a co-culture system with human umbilical vein ECs (HUVECs) from Caucasian American (CA) and AA donors to examine racial differences in monocyte adhesion. An in vitro exercise mimetic model was applied to investigate the potential modulatory effect of HSS. THP-1 adherence to ECs and TNF-induced nuclear factor kappa B (NF-κB) DNA binding were elevated in AA ECs compared to CA ECs, but not significantly. We report no significant racial differences in the expression of the TNFR-I signaling complex. Application of HSS significantly increased the expression and shedding of TNFR-I and the expression of TRAF3, and decreased the expression of TRAF5 in both groups. Our data does not support TNF-induced NF-κB activation as a potential mediator of racial disparity in this model. Other pathways and associated factors activated by the TNFR1 signaling complex are recommended targets for future research.

Role of macronutrient intake in the epigenetics of obesity.

Obesity is caused by a combination of hereditary and environmental factors. Despite extensive study, contemporary through diet, exercise, education, surgery, and pharmacological treatments, no effective long-term solution has been found to this epidemic. Over the last decade, there has been a tremendous advancement in understanding the science of epigenetics, as well as a rise in public interest in learning more about the influence of diet and lifestyle choices on the health of an individual. Without affecting the underlying DNA sequence, epigenetic alterations impact gene expression. Previous animal studies have shown a link between the type of diet and expression or suppression of obesity genes, but there are very few human studies that demonstrate the relationship between dietary intake and obesity gene expression. This review highlights the effects of carbohydrates, lipids, and protein intake from the diet on obesity-related genes.

Multiplexed measurements of salivary fetuin-A, insulin, and adiponectin as potential non-invasive biomarkers in childhood obesity.

BACKGROUND: Obesity increases the risk of developing insulin resistance, diabetes, and cardiovascular disease. The current study is designed to evaluate the association of salivary fetuin-A, insulin, and adiponectin with the obesity measures in children. METHODS: Seventy-six children aged 6-10 years participated in the study. Anthropometric measurements were recorded, and saliva was collected from the participants. Based on the Center for Disease Control and Prevention (CDC), the participants were classified into normal weight (NW), overweight (OW), and obese (OB). Multiplex analysis for salivary markers fetuin-A, insulin, and adiponectin was performed using Luminex performance assay. The diagnostic value of the salivary marker was identified by receiver operating characteristics (ROC) curve, the correlation between obesity measures and markers were performed by regression analysis. RESULTS: Salivary fetuin-A and insulin were significantly increased in OW and OB in comparison to NW. Adiponectin was significantly decreased in the OB compared to NW and OW groups. Fetuin-A and insulin had the highest area under the curve with the best diagnostic value of a biomarker than adiponectin. Fetuin-A and insulin showed a positive association with obesity measures and among the parameters, but adiponectin was inversely associated. CONCLUSIONS: Salivary fetuin-A, insulin, and adiponectin levels are associated with the obesity in elementary school-aged children.

Mitochondrial dysfunction and beneficial effects of mitochondria-targeted small peptide SS-31 in Diabetes Mellitus and Alzheimer's disease.

Diabetes and Alzheimer's disease are common chronic illnesses in the United States and lack clearly demonstrated therapeutics. Mitochondria, the "powerhouse of the cell", is involved in the homeostatic regulation of glucose, energy, and reduction/oxidation reactions. The mitochondria has been associated with the etiology of metabolic and neurological disorders through a dysfunction of regulation of reactive oxygen species. Mitochondria-targeted chemicals, such as the Szeto-Schiller-31 peptide, have advanced therapeutic potential through the inhibition of oxidative stress and the restoration of normal mitochondrial function as compared to traditional antioxidants, such as vitamin E. In this article, we summarize the pathophysiological relevance of the mitochondria and the beneficial effects of Szeto-Schiller-31 peptide in the treatment of Diabetes and Alzheimer's disease.

DNA copy number and structural variation (CNV) contributions to adult and childhood obesity.

In recent years, obesity has reached epidemic proportions globally and has become a major public health concern. The development of obesity is likely caused by several behavioral, environmental, and genetic factors. Genomic variability among individuals is largely due to copy number variations (CNVs). Recent genome-wide association studies (GWAS) have successfully identified many loci containing CNV related to obesity. These obesity-related CNVs are informative to the diagnosis and treatment of genomic diseases. A more comprehensive classification of CNVs may provide the basis for determining how genomic diversity impacts the mechanisms of expression for obesity in children and adults of a variety of genders and ethnicities. In this review, we summarize current knowledge on the relationship between obesity and the CNV of several genomic regions, with an emphasis on genes at the following loci: 11q11, 1p21.1, 10q11.22, 10q26.3, 16q12.2, 16p12.3, and 4q25.

The Effects of Vitamin D on Metabolic Profiles in Women with Polycystic Ovary Syndrome: A Systematic Review.

This systematic review aims to evaluate all epidemiological evidence in the literature linking the effect of vitamin D supplementation to metabolic and hormonal functions in women with polycystic ovary syndrome. The literature search was performed with two databases, namely Medline/PubMed and Web of Science, until 20 May 2019 for both observational and experimental studies concerning relationships between vitamin D and polycystic ovary syndrome. A total of ten studies with randomized, double-blinded, and placebo-controlled trial design from 2008 to 2019 were selected for this review. The inclusion criteria were women 18-45 years of age with polycystic ovary syndrome and comparing the metabolic or endocrine parameters between placebo and vitamin D supplementation groups. A total of ten studies were selected for this review. We found that vitamin D supplementation had a significant effect on insulin metabolism, total serum testosterone, hirsutism, C-reactive protein, and total antioxidant capacity in women with polycystic ovary syndrome. Evidence from available randomized controlled trials suggests that patients with polycystic ovary syndrome should take vitamin D supplementation for the beneficial effect of metabolic profiles. However, future research is needed regarding the beneficial effects in women who are non-obese with polycystic ovary syndrome, as well as more studies with larger sample sizes.

Neuroprotective Effects of Chronic Resveratrol Treatment and Exercise Training in the 3xTg-AD Mouse Model of Alzheimer's Disease.

To date, there is no cure or effective treatment for Alzheimer's disease (AD), a chronic neurodegenerative condition that affects memory, language, and behavior. AD is characterized by neuroinflammation, accumulation of brain amyloid-beta (Aß) oligomers and neurofibrillary tangles, increased neuronal apoptosis, and loss of synaptic function. Promoting regular exercise and a diet containing polyphenols are effective non-pharmacological approaches that prevent the progression of neurodegenerative diseases. In this study, we measured various conformational toxic species of Aß and markers of inflammation, apoptosis, endolysosomal degradation, and neuroprotection after 5 months of exercise training (ET), resveratrol (Resv) treatment, or combination treatment in the 3xTg-AD mouse model of AD. Our main results indicate that Resv decreased neuroinflammation and accumulation of Aß oligomers, increased levels of neurotrophins, synaptic markers, silent information regulator, and decreased markers of apoptosis, autophagy, endolysosomal degradation and ubiquitination in the brains of 3xTg-AD mice. ET improved some markers related to neuroprotection, but when combined with Resv treatment, the benefits achieved were as effective as Resv treatment alone. Our results show that the neuroprotective effects of Resv, ET or Resv and ET are associated with reduced toxicity of Aß oligomers, suppression of neuronal autophagy, decreased apoptosis, and upregulation of key growth-related proteins.

Nerve growth factor receptor TrkA signaling in streptozotocin-induced type 1 diabetes rat brain.

Previous work from our lab demonstrated a new role of TrkA in the insulin signaling pathway. The kinase activity of TrkA is essential for its interaction with the insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) and activation of Akt and Erk5 in PC12 cells. Here we show in brain from streptozotocin (STZ)-induced type 1 diabetic rats that the expression of the inactive proNGF is elevated, whereas the expression of mature NGF is reduced. In addition, tyrosine phosphorylation of TrkA is decreased in STZ-induced diabetes compared to control. Results of the co-immunoprecipitation experiments indicate that the interaction of TrkA with the IR and IRS-1 is also reduced in the brain of diabetic rats. Moreover, tyrosine phosphorylation of the IR and IRS-1, and Akt activation is decreased in STZ diabetes compared to control. Our results suggest that the NGF-TrkA receptor is involved in insulin signaling and is impaired in the brain of STZ-induced diabetic rats.

The effects of popular diets on type 2 diabetes management.

Type 2 diabetes can be managed with the use of diabetes self-management skills. Diet and exercise are essential segments of the lifestyle changes necessary for diabetes management. However, diet recommendations can be complicated in a world full of different diets. This review aims to evaluate the evidence on the effects of three popular diets geared towards diabetes management: low-carbohydrate and ketogenic diet, vegan diet, and the Mediterranean diet. While all three diets have been shown to assist in improving glycaemic control and weight loss, patient adherence, acceptability, and long-term manageability play essential roles in the efficacy of each diet.

High fat diet induces brain insulin resistance and cognitive impairment in mice.

High fat diet-induced obesity is associated with insulin resistance (IR) and other chronic, diet related illnesses, including dementia. Alzheimer disease is the most common form of dementia, and is characterized by the presence of amyloid plaques and neurofibrillary tangles in brain. This study was designed to determine whether diet-induced changes in peripheral insulin sensitivity could contribute to alterations in brain insulin signaling and cognitive functions. Six week old, male C57BL/6NHsd mice were randomly assigned a high fat diet (40% energy from fat) with 42g/L liquid sugar (HFS) added to the drinking water or a normal chow diet (12% energy from fat) for 14weeks. Metabolic phenotypes were characterized for energy expenditure, physical activity, and food intake, and glucose and insulin tolerance tests. In addition, we examined the changes in protein expression related to brain insulin signaling and cognitive function. Mice fed HFS exhibited a statistically significant increase in obesity, and lower glucose and insulin tolerance as compared to animals fed the normal chow diet. In brain, HFS elicited IR as evidenced by a significant decrease in tyrosine phosphorylation of insulin receptor and an increase serine phosphorylation of IRS-1. These changes were accompanied by inflammatory (NFκB, JNK) and stress responses (p38 MAPK, CHOP) in whole brain lysate. In addition, HFS mouse brain exhibited biochemical changes related to increased amyloid beta deposition and neurofibrillary tangle formation, and decreased synaptic plasticity. These results suggested changes in insulin sensitivity might contribute to cognitive impairment associated with the HFS diet in mice.

Amyloid ß-abrogated TrkA ubiquitination in PC12 cells analogous to Alzheimer's disease.

Amyloid beta (Aß) protein is the primary proteinaceous deposit found in the brains of patients with Alzheimer's disease (AD). Evidence suggests that Aß plays a central role in the development of AD pathology. Here, we show in PC12 cells, Aß impairs tropomyosin receptor kinase A (TrkA) ubiquitination, phosphorylation, and its association with p75(NTR), p62, and TRAF6 induced by nerve growth factor. The ubiquitination and tyrosine phosphorylation of TrkA was also found to be impaired in postmortem human AD hippocampus compared to control. Interestingly, the nitrotyrosylation of TrkA was increased in AD hippocampus and this explains why the phosphotyrosylation and ubiquitination of TrkA was impaired. In AD brain, the production of matrix metalloproteinase-7 (MMP-7), which cleaves proNGF, was reduced, thereby leading to the accumulation of pro-NGF and a decrease in the level of active NGF. TrkA signaling events, including Ras/MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways, are deactivated with Aß and in the human AD hippocampus. Findings show that Aß blocks the TrkA ubiquitination and downstream signaling similar to AD hippocampus. Cell survival and differentiation are essential for living organisms. We propose that under normal conditions, nerve growth factor (NGF) leads to Tropomyosin receptor kinase A (TrkA) phosphorylation, ubiquitination and its association with p75(NTR), p62 and TRAF6, thereby promoting cell survival and differentiation. In diseased conditions such as Alzheimer's, proNGF leads to nitrotyrosylation of TrkA, thereby impairing its ubiquitination and downstream signaling which results in apoptosis. TRAF6 = tumor necrosis factor receptor-associated factor 6; Ub = ubiquitin.

Mg2+/Mn2+-dependent phosphatase 1A is involved in regulating pregnane X receptor-mediated cytochrome p450 3A4 gene expression.

Variations in the expression of human pregnane X receptor (hPXR)-mediated cytochrome p450 3A4 (CYP3A4) in liver can alter therapeutic response to a variety of drugs and may lead to potential adverse drug interactions. We sought to determine whether Mg(2+)/Mn(2+)-dependent phosphatase 1A (PPM1A) regulates hPXR-mediated CYP3A4 expression. PPM1A was found to be coimmunoprecipitated with hPXR. Genetic or pharmacologic activation of PPM1A led to a significant increase in hPXR transactivation of CYP3A4 promoter activity. In contrast, knockdown of endogenous PPM1A not only attenuated hPXR transactivation, but also increased proliferation of HepG2 human liver carcinoma cells, suggesting that PPM1A expression levels regulate hPXR, and that PPM1A expression is regulated in a proliferation-dependent manner. Indeed, PPM1A expression and hPXR transactivation were found to be significantly reduced in subconfluent HepG2 cells compared with confluent HepG2 cells, suggesting that both PPM1A expression and hPXR-mediated CYP3A4 expression may be downregulated in proliferating livers. Elevated PPM1A levels led to attenuation of hPXR inhibition by tumor necrosis factor-α and cyclin-dependent kinase-2, which are known to be upregulated and essential during liver regeneration. In mouse regenerating livers, similar to subconfluent HepG2 cells, expression of both PPM1A and the mouse PXR target gene cyp3a11 was found to be downregulated. Our results show that PPM1A can positively regulate PXR activity by counteracting PXR inhibitory signaling pathways that play a major role in liver regeneration. These results implicate a novel role for PPM1A in regulating hPXR-mediated CYP3A4 expression in hepatocytes and may explain a mechanism for CYP3A repression in regenerating livers.

Nerve growth factor receptor TrkA, a new receptor in insulin signaling pathway in PC12 cells.

TrkA is a cell surface transmembrane receptor tyrosine kinase for nerve growth factor (NGF). TrkA has an NPXY motif and kinase regulatory loop similar to insulin receptor (INSR) suggesting that NGF→TrkA signaling might overlap with insulin→INSR signaling. During insulin or NGF stimulation TrkA, insulin receptor substrate-1 (IRS-1), INSR (and presumably other proteins) forms a complex in PC12 cells. In PC12 cells, tyrosine phosphorylation of INSR and IRS-1 is dependent upon the functional TrkA kinase domain. Moreover, expression of TrkA kinase-inactive mutant blocked the activation of Akt and Erk5 in response to insulin or NGF. Based on these data, we propose that TrkA participates in insulin signaling pathway in PC12 cells.

Failure of ubiquitin proteasome system: risk for neurodegenerative diseases.

The ubiquitin proteasome system (UPS) is the primary proteolytic quality control system in cells and has an essential function in the nervous system. UPS dysfunction has been linked to neurodegenerative conditions, including Alzheimer's, Parkinson's and Huntington's diseases. The pathology of neurodegenerative diseases is characterized by the abnormal accumulation of insoluble protein aggregates or inclusion bodies within neurons. The failure or dysregulation of the UPS prevents the degradation of misfolded/aberrant proteins, leading to deficient synaptic function that eventually affects the nervous system. In this review, we discuss the UPS and its physiological roles in the nervous system, its influence on neuronal function, and how UPS dysfunction contributes to the development of neurodegenerative diseases.

Omega-3 Supplementation and Its Effects on Osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease characterized by the destruction of the articular cartilage, resulting in a pro-inflammatory response. The progression of OA is multifactorial and is influenced by the underlying cause of inflammation, which includes but is not limited to trauma, metabolism, biology, comorbidities, and biomechanics. Although articular cartilage is the main tissue affected in osteoarthritis, the chronic inflammatory environment negatively influences the surrounding synovium, ligaments, and subchondral bone, further limiting their functional abilities and enhancing symptoms of OA. Treatment for osteoarthritis remains inconsistent due to the inability to determine the underlying mechanism of disease onset, severity of symptoms, and complicating comorbidities. In recent years, diet and nutritional supplements have gained interest regarding slowing the disease process, prevention, and treatment of OA. This is due to their anti-inflammatory properties, which result in a positive influence on pain, joint mobility, and cartilage formation. More specifically, omega-3 polyunsaturated fatty acids (PUFA) have demonstrated an influential role in the progression of OA, resulting in the reduction of cartilage destruction, inhibition of pro-inflammatory cytokine cascades, and production of oxylipins that promote anti-inflammatory pathways. The present review is focused on the assessment of evidence explaining the inflammatory processes of osteoarthritis and the influence of omega-3 supplementation to modulate the progression of osteoarthritis.

The Importance of Sleep in Overcoming Childhood Obesity and Reshaping Epigenetics.

The development of childhood obesity is a complex process influenced by a combination of genetic predisposition and environmental factors, such as sleep, diet, physical activity, and socioeconomic status. Long-term solutions for decreasing the risk of childhood obesity remain elusive, despite significant advancements in promoting health and well-being in school and at home. Challenges persist in areas such as adherence to interventions, addressing underlying social determinants, and individual differences in response to treatment. Over the last decade, there has been significant progress in epigenetics, along with increased curiosity in gaining insights into how sleep and lifestyle decisions impact an individual's health. Epigenetic modifications affect the expression of genes without causing changes to the fundamental DNA sequence. In recent years, numerous research studies have explored the correlation between sleep and the epigenome, giving a better understanding of DNA methylation, histone modification, and non-coding RNAs. Although significant findings have been made about the influence of sleep on epigenetics, a notable gap exists in the literature concerning sleep-related genes specifically associated with childhood obesity. Consequently, it is crucial to delve deeper into this area to enhance our understanding. Therefore, this review primarily focuses on the connection between sleep patterns and epigenetic modifications in genes related to childhood obesity. Exploring the interplay between sleep, epigenetics, and childhood obesity can potentially contribute to improved overall health outcomes. This comprehensive review encompasses studies focusing on sleep-related genes linked to obesity.

Mitochondrial Adaptation in Skeletal Muscle: Impact of Obesity, Caloric Restriction, and Dietary Compounds.

PURPOSE OF REVIEW: The global obesity epidemic has become a major public health concern, necessitating comprehensive research into its adverse effects on various tissues within the human body. Among these tissues, skeletal muscle has gained attention due to its susceptibility to obesity-related alterations. Mitochondria are primary source of energy production in the skeletal muscle. Healthy skeletal muscle maintains constant mitochondrial content through continuous cycle of synthesis and degradation. However, obesity has been shown to disrupt this intricate balance. This review summarizes recent findings on the impact of obesity on skeletal muscle mitochondria structure and function. In addition, we summarize the molecular mechanism of mitochondrial quality control systems and how obesity impacts these systems. RECENT FINDINGS: Recent findings show various interventions aimed at mitigating mitochondrial dysfunction in obese model, encompassing strategies including caloric restriction and various dietary compounds. Obesity has deleterious effect on skeletal muscle mitochondria by disrupting mitochondrial biogenesis and dynamics. Caloric restriction, omega-3 fatty acids, resveratrol, and other dietary compounds enhance mitochondrial function and present promising therapeutic opportunities.