Showing papers by "Clay F. Semenkovich published in 2020"

Satellite glial cells promote regenerative growth in sensory neurons.

Abstract: Peripheral sensory neurons regenerate their axon after nerve injury to enable functional recovery. Intrinsic mechanisms operating in sensory neurons are known to regulate nerve repair, but whether satellite glial cells (SGC), which completely envelop the neuronal soma, contribute to nerve regeneration remains unexplored. Using a single cell RNAseq approach, we reveal that SGC are distinct from Schwann cells and share similarities with astrocytes. Nerve injury elicits changes in the expression of genes related to fatty acid synthesis and peroxisome proliferator-activated receptor (PPARα) signaling. Conditional deletion of fatty acid synthase (Fasn) in SGC impairs axon regeneration. The PPARα agonist fenofibrate rescues the impaired axon regeneration in mice lacking Fasn in SGC. These results indicate that PPARα activity downstream of FASN in SGC contributes to promote axon regeneration in adult peripheral nerves and highlight that the sensory neuron and its surrounding glial coat form a functional unit that orchestrates nerve repair.

Satellite glial cells promote regenerative growth in sensory neurons

Abstract: SUMMARY Peripheral sensory neurons switch to a regenerative state after nerve injury to enable axon regeneration and functional recovery. Intrinsic mechanisms operating in sensory neurons are known to regulate nerve repair, but whether satellite glial cells (SGC), which completely envelop the neuronal soma, undergo injury-evoked transcriptional changes and contribute to nerve regeneration remains unexplored. This is largely due to the lack of molecular and genetic tools to study SGC. Using a single cell RNAseq approach to define the transcriptional profile of SGC in naive and injured conditions, we reveal that these cells are distinct from Schwann cells and share similarities with astrocytes. We find that nerve injury elicits gene expression changes in SGC, which are related to fatty acid synthesis and peroxisome proliferator-activated receptor (PPARα) signaling. Conditional deletion of Fatty acid synthase (Fasn), the committed enzyme in de novo fatty acid synthesis, in SGC, impairs axon regeneration. The PPARα agonist fenofibrate rescues the impaired axon regeneration in mice lacking Fasn in SGC, indicating that PPARα functions downstream of fatty acid synthesis in SGC to promote axon regeneration. These results identify fatty acid synthesis in SGC as a fundamental novel mechanism mediating axon regeneration in adult peripheral nerves. These results also highlight that the sensory neuron and its surrounding glial coat form a functional unit that orchestrates nerve repair.

Endothelial Palmitoylation Cycling Coordinates Vessel Remodeling in Peripheral Artery Disease.

Abstract: Rationale: Peripheral artery disease, common in metabolic syndrome and diabetes mellitus, responds poorly to medical interventions and is characterized by chronic vessel immaturity leading to lower...

Hepatic lipids promote liver metastasis.

Abstract: Obesity predisposes to cancer and a virtual universality of nonalcoholic fatty liver disease (NAFLD). However, the impact of hepatic steatosis on liver metastasis is enigmatic. We find that while control mice were relatively resistant to hepatic metastasis, those which were lipodystrophic or obese, with NAFLD, had a dramatic increase in breast cancer and melanoma liver metastases. NAFLD promotes liver metastasis by reciprocal activation initiated by tumor-induced triglyceride lipolysis in juxtaposed hepatocytes. The lipolytic products are transferred to cancer cells via fatty acid transporter protein 1, where they are metabolized by mitochondrial oxidation to promote tumor growth. The histology of human liver metastasis indicated the same occurs in humans. Furthermore, comparison of isolates of normal and fatty liver established that steatotic lipids had enhanced tumor-stimulating capacity. Normalization of glucose metabolism by metformin did not reduce steatosis-induced metastasis, establishing the process is not mediated by the metabolic syndrome. Alternatively, eradication of NAFLD in lipodystrophic mice by adipose tissue transplantation reduced breast cancer metastasis to that of control mice, indicating the steatosis-induced predisposition is reversible.

Association of Retinopathy and Insulin Resistance: NHANES 2005-2008.

Abstract: Purpose: In animal models, insulin resistance without severe hyperglycemia is associated with retinopathy; however, corroborating data in humans are lacking. This study aims to investigate the prevalence of retinopathy in a population without diabetes and evaluate the association of insulin resistance and retinopathy within this group.Methods: The study population included 1914 adults age ≥40 without diabetes who were assigned to the morning, fasted group in the National Health and Nutrition Examination Survey 2005-2008, conducted by the Centers for Disease Control. Retinopathy was determined using fundus photos independently graded by a reading center and insulin resistance was determined using the homeostatic model of insulin resistance.Results: Prevalence of retinopathy in those without diabetes was survey design adjusted 9.4% (174/1914). In multivariable analyses, retinopathy was associated with insulin resistance (HOMA-IR OR: 1.09, 95% CI: 1.03, 1.16; p = .0030), male gender (OR: 1.39, 95% CI: 1.04, 1.85; p = .0267), and age (OR: 1.03, 95% CI: 1.01, 1.05; p = .0203).Conclusions: Insulin resistance in the absence of overt hyperglycemia could be an early driver of retinopathy.

Fenofibrate Reduces the Severity of Neuroretinopathy in a Type 2 Model of Diabetes without Inducing Peroxisome Proliferator-Activated Receptor Alpha-Dependent Retinal Gene Expression.

Abstract: Fenofibrate slows the progression of clinical diabetic retinopathy (DR), but its mechanism of action in the retina remains unclear. Fenofibrate is a known agonist of peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor critical for regulating metabolism, inflammation and oxidative stress. Using a DR mouse model, db/db, we tested the hypothesis that fenofibrate slows early DR progression by activating PPARα in the retina. Relative to healthy littermates, six-month-old db/db mice exhibited elevated serum triglycerides and cholesterol, retinal gliosis, and electroretinography (ERG) changes including reduced b-wave amplitudes and delayed oscillatory potentials. These pathologic changes in the retina were improved by oral fenofibrate. However, fenofibrate did not induce PPARα target gene expression in whole retina or isolated Muller glia. The capacity of the retina to respond to PPARα was further tested by delivering the PPARα agonist GW590735 to the intraperitoneal or intravitreous space in mice carrying the peroxisome proliferator response element (PPRE)-luciferase reporter. We observed strong induction of the reporter in the liver, but no induction in the retina. In summary, fenofibrate treatment of db/db mice prevents the development of early DR but is not associated with induction of PPARα in the retina.