title: Diet-induced obesity and low testosterone increase neuroinflammation and impair neural function.
abstract: BACKGROUND
  Low testosterone and obesity are independent risk factors for dysfunction of the nervous system including neurodegenerative disorders such as Alzheimer's disease (AD). In this study, we investigate the independent and cooperative interactions of testosterone and diet-induced obesity on metabolic, inflammatory, and neural health indices in the central and peripheral nervous systems.
  
  
  METHODS
  Male C57B6/J mice were maintained on normal or high-fat diet under varying testosterone conditions for a four-month treatment period, after which metabolic indices were measured and RNA isolated from cerebral cortex and sciatic nerve. Cortices were used to generate mixed glial cultures, upon which embryonic cerebrocortical neurons were co-cultured for assessment of neuron survival and neurite outgrowth. Peripheral nerve damage was determined using paw-withdrawal assay, myelin sheath protein expression levels, and Na+,K+-ATPase activity levels.
  
  
  RESULTS
  Our results demonstrate that detrimental effects on both metabolic (blood glucose, insulin sensitivity) and proinflammatory (cytokine expression) responses caused by diet-induced obesity are exacerbated by testosterone depletion. Mixed glial cultures generated from obese mice retain elevated cytokine expression, although low testosterone effects do not persist ex vivo. Primary neurons co-cultured with glial cultures generated from high-fat fed animals exhibit reduced survival and poorer neurite outgrowth. In addition, low testosterone and diet-induced obesity combine to increase inflammation and evidence of nerve damage in the peripheral nervous system.
  
  
  CONCLUSIONS
  Testosterone and diet-induced obesity independently and cooperatively regulate neuroinflammation in central and peripheral nervous systems, which may contribute to observed impairments in neural health. Together, our findings suggest that low testosterone and obesity are interactive regulators of neuroinflammation that, in combination with adipose-derived inflammatory pathways and other factors, increase the risk of downstream disorders including type 2 diabetes and Alzheimer's disease.
authors.forename: Anusha
authors.initials: A
authors.lastname: Jayaraman
authors.forename: Daniella
authors.initials: D
authors.lastname: Lent-Schochet
authors.affiliation: Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles 90089, CA, USA. cjpike@usc.edu.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Pike
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000503:physiopathology; D007249:Inflammation / Q000139:chemically induced* / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009765:Obesity / Q000139:chemically induced* / Q000188:drug therapy*; D009919:Orchiectomy; D017288:Pain Threshold / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D013739:Testosterone; D000254:Sodium-Potassium-Exchanging ATPase