title: High-fat diet feeding causes rapid, non-apoptotic cleavage of caspase-3 in astrocytes.
abstract: Astrocytes respond to multiple forms of central nervous system (CNS) injury by entering a reactive state characterized by morphological changes and a specific pattern of altered protein expression. Termed astrogliosis, this response has been shown to strongly influence the injury response and functional recovery of CNS tissues. This pattern of CNS inflammation and injury associated with astrogliosis has recently been found to occur in the energy homeostasis centers of the hypothalamus during diet-induced obesity (DIO) in rodent models, but the characterization of the astrocyte response remains incomplete. Here, we report that astrocytes in the mediobasal hypothalamus respond robustly and rapidly to purified high-fat diet (HFD) feeding by cleaving caspase-3, a protease whose cleavage is often associated with apoptosis. Although obesity develops in HFD-fed rats by day 14, caspase-3 cleavage occurs by day 3, prior to the development of obesity, suggesting the possibility that it could play a causal role in the hypothalamic neuropathology and fat gain observed in DIO. Caspase-3 cleavage is not associated with an increase in the rate of apoptosis, as determined by TUNEL staining, suggesting it plays a non-apoptotic role analogous to the response to excitotoxic neuron injury. Our results indicate that astrocytes in the mediobasal hypothalamus respond rapidly and robustly to HFD feeding, activating caspase-3 in the absence of apoptosis, a process that has the potential to influence the course of DIO.
authors.affiliation: Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, Diabetes and Obesity Center of Excellence, University of Washington, UW Medicine at South Lake Union, 850 Republican Street, Box 358055, Seattle, WA 98109, USA. guyenet@uw.edu
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Guyenet
authors.forename: Hong T
authors.initials: HT
authors.lastname: Nguyen
authors.forename: Bang H
authors.initials: BH
authors.lastname: Hwang
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
authors.forename: Denis G
authors.initials: DG
authors.lastname: Baskin
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Thaler
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001253:Astrocytes / Q000378:metabolism*; D001823:Body Composition / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007031:Hypothalamus / Q000473:pathology*; D020287:In Situ Nick-End Labeling; D008297:Male; D009765:Obesity / Q000139:chemically induced* / Q000473:pathology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D005904:Glial Fibrillary Acidic Protein; D053148:Caspase 3; D010751:Phosphopyruvate Hydratase
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