title: Effects of diet-induced obesity and voluntary exercise in a tauopathy mouse model: implications of persistent hyperleptinemia and enhanced astrocytic leptin receptor expression.
abstract: The number of patients with Alzheimer's disease (AD) is increasing worldwide, and available drugs have shown limited efficacy. Hence, preventive interventions and treatments for presymptomatic AD are currently considered very important. Obesity rates have also been increasing dramatically and it is an independent risk factor of AD. Therefore, for the prevention of AD, it is important to elucidate the pathomechanism between obesity and AD. We generated high calorie diet (HCD)-induced obese tauopathy model mice (PS19), which showed hyperleptinemia but limited insulin resistance. HCD enhanced tau pathology and glial activation. Conversely, voluntary exercise with a running wheel normalized the serum leptin concentration without reducing body weight, and restored the pathological changes induced by HCD. Thus, we speculated that persistent hyperleptinemia played an important role in accelerating pathological changes in PS19 mice. Leptin primarily regulates food intake and body weight via leptin receptor b (LepRb). Interestingly, the nuclear staining for p-STAT3, which was activated by LepRb, was decreased in hippocampal neurons in HCD PS19 mice, indicating leptin resistance. Meanwhile, astroglial activation and the astrocytic expression of a short LepR isoform, LepRa, were enhanced in the hippocampus of HCD PS19 mice. Real-time PCR analysis demonstrated that leptin increased mRNA levels for pro-inflammatory cytokines including IL-1β and TNF-α in primary cultured astrocytes from wild type and LepRb-deficient mice. These observations suggest that persistent hyperleptinemia caused by obesity induces astrocytic activation, astrocytic leptin hypersensitivity with enhanced LepRa expression, and enhanced inflammation, consequently accelerating tau pathology in PS19 mice.
authors.affiliation: Department of Neurology, School of Graduate Medicine, Chiba University, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Koga
authors.affiliation: Laboratory for Neurodegenerative Disorder Research, Clinical Research Center, Chiba-East National Hospital, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Kojima
authors.affiliation: Laboratory for Neurodegenerative Disorder Research, Clinical Research Center, Chiba-East National Hospital, Japan; Department of Neurology, Chiba-East National Hospital, Japan.
authors.forename: Chieko
authors.initials: C
authors.lastname: Ishikawa
authors.affiliation: Department of Neurology, School of Graduate Medicine, Chiba University, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuwabara
authors.affiliation: Department of Neurology, Chiba-East National Hospital, Japan; Department of Neurology, School of Graduate Medicine, Chiba University, Japan.
authors.forename: Kimihito
authors.initials: K
authors.lastname: Arai
authors.affiliation: Laboratory for Neurodegenerative Disorder Research, Clinical Research Center, Chiba-East National Hospital, Japan; Department of Neurology, Chiba-East National Hospital, Japan; Department of Neurology, School of Graduate Medicine, Chiba University, Japan. Electronic address: neuroyy@cehpnet.com.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Yoshiyama
mesh_terms: D000367:Age Factors; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001835:Body Weight; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005081:Exercise Therapy / Q000379:methods*; D006801:Humans; D065906:Hyperlactatemia / Q000209:etiology*; D020738:Leptin / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000503:physiopathology*; D010766:Phosphorylation / Q000235:genetics; D012333:RNA, Messenger; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D024801:Tauopathies / Q000235:genetics / Q000473:pathology / Q000534:rehabilitation; D016875:tau Proteins / Q000235:genetics
chemical_list: D020738:Leptin; C054369:MAPT protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D016875:tau Proteins
keywords: Astrocyte; Leptin; Neuroinflammation; Obesity; Tau