title: Time-dependent behavioral, neurochemical, and metabolic dysregulation in female C57BL/6 mice caused by chronic high-fat diet intake.
abstract: High-fat diet (HFD) induced obesity is associated not only with metabolic dysregulation, e.g., impaired glucose homeostasis and insulin sensitivity, but also with neurological dysfunction manifested with aberrant behavior and/or neurotransmitter imbalance. Most studies have examined HFD's effects predominantly in male subjects, either in the periphery or on the brain, in isolation and after a finite feeding period. In this study, we evaluated the time-course of selected metabolic, behavioral, and neurochemical effects of HFD intake in parallel and at multiple time points in female (C57BL/6) mice. Peripheral effects were evaluated at three feeding intervals (short: 5-6 weeks, long: 20-22 weeks, and prolonged: 33-36 weeks). Central effects were evaluated only after long and prolonged feeding durations; we have previously reported those effects after the short (5-6 weeks) feeding duration. Ongoing HFD feeding resulted in an obese phenotype characterized by increased visceral adiposity and, after prolonged HFD intake, an increase in liver and kidney weights. Peripherally, 5 weeks of HFD intake was sufficient to impair glucose tolerance significantly, with the deleterious effects of HFD being greater with prolonged intake. Similarly, 5 weeks of HFD consumption was sufficient to impair insulin sensitivity. However, sensitivity to insulin after prolonged HFD intake was not different between control, low-fat diet (LFD) and HFD-fed mice, most likely due to age-dependent decrease in insulin sensitivity in the LFD-fed mice. HFD intake also induced bi-phasic hepatic inflammation and it increased gut permeability. Behaviorally, prolonged intake of HFD caused mice to be hypoactive and bury fewer marbles in a marble burying task; the latter was associated with significantly impaired hippocampal serotonin homeostasis. Cognitive (short-term recognition memory) function of mice was unaffected by chronic HFD feeding. Considering our prior findings of short-term (5-6 weeks) HFD-induced central (hyperactivity/anxiety and altered ventral hippocampal neurochemistry) effects and our current results, it seems that in female mice some metabolic/inflammatory dysregulations caused by HFD, such as gut permeability, appear early and persist, whereas others, such as glucose intolerance, are exaggerated with continuous HFD feeding; behaviorally, prolonged HFD consumption mainly affects locomotor activity and anxiety-like responses, likely due to the advanced obesity phenotype; neurochemically, the serotonergic system appears to be most sensitive to continued HFD feeding.
authors: Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA, 30602, USA.
authors: Saritha
authors: S
authors: Krishna
authors: Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA, 30602, USA.
authors: Zhoumeng
authors: Z
authors: Lin
authors: Department of Foods and Nutrition, College of Family and Consumer Sciences, University of Georgia, Athens, GA, 30602, USA.
authors: Claire B
authors: CB
authors: de La Serre
authors: Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA, 30602, USA.
authors: John J
authors: JJ
authors: Wagner
authors: Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, 30602, USA.
authors: Donald H
authors: DH
authors: Harn
authors: Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA, 30602, USA.
authors: Lacey M
authors: LM
authors: Pepples
authors: Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA, 30602, USA.
authors: Dylan M
authors: DM
authors: Djani
authors: Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA, 30602, USA.
authors: Matthew T
authors: MT
authors: Weber
authors: Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, 30602, USA.
authors: Leena
authors: L
authors: Srivastava
authors: Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA, 30602, USA. Electronic address: filipov@uga.edu.
authors: Nikolay M
authors: NM
authors: Filipov
mesh_terms: D000367:Age Factors; D000818:Animals; D002199:Capillary Permeability; D059305:Diet, High-Fat / Q000009:adverse effects*; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D006948:Hyperkinesis / Q000209:etiology*; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008124:Locomotion / Q000502:physiology; D008659:Metabolic Diseases / Q000209:etiology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019964:Mood Disorders / Q000209:etiology*; D053580:Muscle Strength; D009448:Neurochemistry; D018377:Neurotransmitter Agents / Q000378:metabolism; D013550:Swimming / Q000523:psychology; D013997:Time Factors
chemical_list: D018377:Neurotransmitter Agents
keywords: Anxiety; Glucose intolerance; Hepatic inflammation; High-fat diet; Hypoactivity; Insulin sensitivity