title: Thermoneutral housing is a critical factor for immune function and diet-induced obesity in C57BL/6 nude mice.
abstract: OBJECTIVE
  Obesity-related cancers represent public health burdens of the first order. Nevertheless, suitable mouse models to unravel molecular mechanisms linking obesity to human cancer are still not available. One translational model is the immunocompromised Foxn1 (winged-helix/forkead transcription factor) nude mouse transplanted with human tumor xenografts. However, most xenograft studies are conducted in nude mice on an in-bred BALB/c background that entails protection from diet-induced obesity. To overcome such resistance to obesity and its sequelae, we here propose the dual strategy of utilizing Foxn1 nude mice on a C57BL/6 background and housing them at their thermoneutral zone.
  
  
  METHODS
  C57BL/6 nude and corresponding wild-type mice, housed at 23 or 33 °C, were subjected to either low-fat diet or high-fat diet (HFD). Energy expenditure, locomotor activity, body core temperature, respiratory quotient as well as food and water intake were analyzed using indirect calorimetry. Immune function at different housing temperatures was assessed by using an in vivo cytokine capture assay.
  
  
  RESULTS
  Our data clearly demonstrate that conventional housing protects C57BL/6 nude mice from HFD-induced obesity, potentially via increased energy expenditure. In contrast, HFD-fed C57BL/6 nude mice housed at thermoneutral conditions develop adiposity, increased hepatic triglyceride accumulation, adipose tissue inflammation and glucose intolerance. Moreover, increased circulating levels of lipopolysaccharide-driven cytokines suggest a greatly enhanced immune response in C57BL/6 nude mice housed at thermoneutrality.
  
  
  CONCLUSIONS
  Our data reveals mild cold stress as a major modulator for energy and body weight homeostasis as well as immune function in C57BL/6 nude mice. Adjusting housing temperatures to the thermoneutral zone may ultimately be key to successfully study growth and progression of human tumors in a diet-induced obese environment.
authors.affiliation: 1] Division of Metabolism and Cancer, Institute for Diabetes and Obesity, Helmholtz Centre Munich, Neuherberg, Germany [2] Division of Immunobiology, Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: K
authors.initials: K
authors.lastname: Stemmer
authors.affiliation: Division of Metabolism and Cancer, Institute for Diabetes and Obesity, Helmholtz Centre Munich, Neuherberg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Kotzbeck
authors.affiliation: Division of Metabolism and Cancer, Institute for Diabetes and Obesity, Helmholtz Centre Munich, Neuherberg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Zani
authors.affiliation: Division of Metabolism and Cancer, Institute for Diabetes and Obesity, Helmholtz Centre Munich, Neuherberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Division of Metabolism and Cancer, Institute for Diabetes and Obesity, Helmholtz Centre Munich, Neuherberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Neff
authors.affiliation: Division of Molecular Pharmacology, Institute for Diabetes and Obesity, Helmholtz Centre Munich, Neuherberg, Germany.
authors.forename: T D
authors.initials: TD
authors.lastname: Müller
authors.affiliation: Division of Nutrition Biology, Institute for Diabetes and Obesity, Helmholtz Centre Munich, Neuherberg, Germany.
authors.forename: P T
authors.initials: PT
authors.lastname: Pfluger
authors.affiliation: 1] Division of Immunobiology, Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, Cincinnati, OH, USA [2] Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Seeley
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Divanovic
mesh_terms: D000818:Animals; D001835:Body Weight; D003080:Cold Temperature; D059305:Diet, High-Fat; D004734:Energy Metabolism; D006799:Housing, Animal / Q000592:standards*; D016867:Immunocompromised Host; D007249:Inflammation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D013312:Stress, Physiological; D013696:Temperature; D014183:Transplantation, Heterologous / Q000379:methods