Identification of TRPV4 as a Regulator of Adipose Oxidative Metabolism, Inflammation and Energy Homeostasis by a Chemical Biology Approach

$PGC1\alpha$ is a key transcriptional coregulator of mitochondrial biogenesis, oxidative metabolism and thermogenesis. We developed a quantitative high throughput screen to identify small molecules that can induce $PGC1\alpha$ expression in adipocytes. Small molecules antagonizing the TRPVs (Transient Receptor Potential Vanilloid), a family of ion channels, induced $PGC1\alpha$ expression in adipocytes. In particular, inhibition of TRPV4 increased expression of $PGC1\alpha$, UCP1 and cellular respiration; conversely, chemical activation of TRPV4 repressed this pathway. Blocking TRPV4 in cultured adipocytes also reduced the expression of multiple proinflammatory genes that are involved in the development of insulin resistance. These effects of TRPV4 were mediated by the activation of ERK1/2. Finally, mice with a null mutation for TRPV4 showed higher energy expenditure with no change in movement or food intake, and were protected from diet-induced obesity, adipose inflammation and insulin resistance. This study links TRPV4 to robust pathways that offer therapeutic potential in obesity and related metabolic diseases

Modulation of nitric oxide synthase I transcription by Tau and Alpha-Synuclein and its relevance to Alzheimer\u27s and Parkinson\u27s diseases

Alzheimer\u27s Disease (AD) and Parkinson\u27s Disease (PD) are both progressive neurodegenerative disorders that affect millions of Americans and for which there are no cures. AD can significantly impair the ability to think, remember, communicate, and carry out daily activities, while PD can affect motor functions such as balance, coordination, and the ability to speak. Intracellular protein aggregation is a hallmark of both diseases, with AD being characterized by the build up of neurofibrillary tangles composed of misfolded tau protein and PD being characterized by Lewy bodies composed of alpha-synuclein. Both normal tau and alpha-synuclein can localize to the nucleus; however, their nuclear roles have not been fully elucidated. These proteins bind and stabilize alternative DNA structures, which form most readily at purine-pyrimidine repeats. The 1f promoter of the Nitric Oxide Synthase I (NOSI) gene, which is misregulated in both AD and PD, contains one such repeat. This NOSI repeat is polymorphic and has the sequence (TG)mTA(TG)n where m and n can vary from individual to individual. Genotyping shows that shorter dinucleotide polymorphisms are associated with AD and PD. Promoters with shorter repeats also have decreased transcriptional expression compared to promoters with larger repeats. Because tau and alpha-synuclein can bind such repeats, we hypothesize that tau and alpha-synuclein may modulate NOSI transcription through the (TG)nTA(TG)m repeat. Reporter genes directed by the NOSI 1f promoter with and without the (TG)nTA(TG)m repeat region were transfected into human neuroblastoma cells (SK-N-MC) and human cervical cancer cells (HeLa) that express varying levels of tau and alpha-synuclein. Promoters with the TG repeat directed approximately two-fold changes in reporter gene expression, while promoters without the TG repeat caused no change in expression. These findings suggest that tau and alpha-synuclein modulate NOSI expression through interaction with a dinucleotide polymorphism associated with disease development

Gene expression of key regulators of mitochondrial biogenesis is sex dependent in mice with growth hormone receptor deletion in liver

Mitochondrial biogenesis is an essential process for cell viability. Mice with disruption of the growth hormone receptor (GHR) gene (Ghr gene) in the liver (LiGHRKO), in contrast to long-lived mice with global deletion of the Ghr gene (GHRKO), are characterized by lack of improved insulin sensitivity and severe hepatic steatosis. Tissue-specific disruption of the GHR in liver results in a mouse model with dramatically altered GH/IGF1 axis. We have previously shown increased levels of key regulators of mitochondrial biogenesis in insulin-sensitive GHRKO mice. The aim of the present study is to assess, using real-time PCR, the gene expression of key regulators of mitochondrial biogenesis (Pgc1 alpha, Ampk, Sirt1, Nrf2 and Mfn2) and a marker of mitochondrial activity (CoxIV) in brains, kidneys and livers of male and female LiGHRKO and wild-type (WT) mice. There were significant differences between males and females. In the brain, expression of Pgc1 alpha, Ampk, Sirt1, Nrf2 and Mfn2 was lower in pooled females compared to pooled males. In the kidneys, expression of Ampk and Sirt1 was also lower in female mice. In the liver, no differences between males and females were observed. Sexual dimorphism may play an important role in regulating the biogenesis of mitochondria

Physical activity and redox balance in the elderly: Signal transduction mechanisms

Reactive Oxygen Species (ROS) are molecules naturally produced by cells. If their levels are too high, the cellular antioxidant machinery intervenes to bring back their quantity to physiological conditions. Since aging often induces malfunctioning in this machinery, ROS are considered an effective cause of age-associated diseases. Exercise stimulates ROS production on one side, and the antioxidant systems on the other side. The effects of exercise on oxidative stress markers have been shown in blood, vascular tissue, brain, cardiac and skeletal muscle, both in young and aged people. However, the intensity and volume of exercise and the individual subject characteristics are important to envisage future strategies to adequately personalize the balance of the oxidant/antioxidant environment. Here, we reviewed the literature that deals with the effects of physical activity on redox balance in young and aged people, with insights into the molecular mechanisms involved. Although many molecular pathways are involved, we are still far from a comprehensive view of the mechanisms that stand behind the effects of physical activity during aging. Although we believe that future precision medicine will be able to transform exercise administration from wellness to targeted prevention, as yet we admit that the topic is still in its infancy

Effects of HIV Proteins on Macrophage Response to MAI

https://digitalcommons.unmc.edu/surp2023/1006/thumbnail.jp

Mild Mitochondrial Uncoupling and Calorie Restriction Increase Fasting eNOS, Akt and Mitochondrial Biogenesis

Enhanced mitochondrial biogenesis promoted by eNOS activation is believed to play a central role in the beneficial effects of calorie restriction (CR). Since treatment of mice with dinitrophenol (DNP) promotes health and lifespan benefits similar to those observed in CR, we hypothesized that it could also impact biogenesis. We found that DNP and CR increase citrate synthase activity, PGC-1α, cytochrome c oxidase and mitofusin-2 expression, as well as fasting plasma levels of NO• products. In addition, eNOS and Akt phosphorylation in skeletal muscle and visceral adipose tissue was activated in fasting CR and DNP animals. Overall, our results indicate that systemic mild uncoupling activates eNOS and Akt-dependent pathways leading to mitochondrial biogenesis

Resveratrol treatment reduces the appearance of tubular aggregates and improves the resistance to fatigue in aging mice skeletal muscles

Resveratrol (RES) is a polyphenolic compound found in grapes, peanuts, and in some berries. RES has been reported to exhibit antioxidant, anti-inflammatory, anti-proliferative properties, and to target mitochondrial- related pathways in mammalian cells and animal models. Therefore, RES is currently advised as supplement in the diet of elderly individuals. Although it is hypothesized that some of RES beneficial actions likely arise from its action on the skeletal muscle, the investigation of RES effects on this tissue remains still elusive. This study reports the effects of a 0,04% RES-supplemented diet for six months, on the skeletal muscle properties of C57/ BL6 aging mice. The analysis of the morphology, protein expression, and functional-mechanical properties of selected skeletal muscles in treated compared to control mice, revealed that treated animals presented less tubular aggregates and a better resistance to fatigue in an ex-vivo contraction test, suggesting RES as a good candidate to reduce age-related alterations in muscle