Abstract
Background
Prolonged over-consumption of a high-fat diet (HFD) commonly leads to obesity and insulin resistance. However, even 3 days of HFD consumption has been linked to inflammation within the key homeostatic brain region, the hypothalamus.
Methods
Mice were fed either a low-fat diet (LFD) or HFD containing 10% or 60% (Kcal) respectively from fat for 3 days. Mice were weighed, food intake measured and glucose tolerance calculated using intraperitoneal glucose tolerance tests (IPGTT). Proteomic analysis was carried out to determine if hypothalamic proteins were changed by a HFD. The direct effects of dietary fatty acids on mitochondrial morphology and on one of the proteins most changed by a HFD, dihydropyrimidinase-related protein 2 (DRP-2) a microtubule-associated protein which regulates microtubule dynamics, were also tested in mHypoE-N42 (N42) neuronal cells challenged with palmitic acid (PA) and oleic acid (OA).
Results
Mice on the HFD, as expected, showed increased adiposity and glucose intolerance. Hypothalamic proteomic analysis revealed changes in 104 spots after 3 days on HFD, which, when identified by LC/MS/MS, were found to represent 78 proteins mainly associated with cytoskeleton and synaptic plasticity, stress response, glucose metabolism and mitochondrial function. Over half of the changed proteins have also been reported to be changed in neurodegenerative conditions such as Alzheimer’s disease. Also,in N42 neurons mitochondrial morphology and DRP-2 levels were altered by PA but not by OA.
Conclusion
These results demonstrate that within 3 days, there is a relatively large effect of HFD on the hypothalamic proteome indicative of cellular stress, altered synaptic plasticity and mitochondrial function, but not inflammation. Changes in N42 cells show an effect of PA but not OA on DRP-2 and on mitochondrial morphology indicating that long-chain saturated fatty acids damage neuronal function.
Prolonged over-consumption of a high-fat diet (HFD) commonly leads to obesity and insulin resistance. However, even 3 days of HFD consumption has been linked to inflammation within the key homeostatic brain region, the hypothalamus.
Methods
Mice were fed either a low-fat diet (LFD) or HFD containing 10% or 60% (Kcal) respectively from fat for 3 days. Mice were weighed, food intake measured and glucose tolerance calculated using intraperitoneal glucose tolerance tests (IPGTT). Proteomic analysis was carried out to determine if hypothalamic proteins were changed by a HFD. The direct effects of dietary fatty acids on mitochondrial morphology and on one of the proteins most changed by a HFD, dihydropyrimidinase-related protein 2 (DRP-2) a microtubule-associated protein which regulates microtubule dynamics, were also tested in mHypoE-N42 (N42) neuronal cells challenged with palmitic acid (PA) and oleic acid (OA).
Results
Mice on the HFD, as expected, showed increased adiposity and glucose intolerance. Hypothalamic proteomic analysis revealed changes in 104 spots after 3 days on HFD, which, when identified by LC/MS/MS, were found to represent 78 proteins mainly associated with cytoskeleton and synaptic plasticity, stress response, glucose metabolism and mitochondrial function. Over half of the changed proteins have also been reported to be changed in neurodegenerative conditions such as Alzheimer’s disease. Also,in N42 neurons mitochondrial morphology and DRP-2 levels were altered by PA but not by OA.
Conclusion
These results demonstrate that within 3 days, there is a relatively large effect of HFD on the hypothalamic proteome indicative of cellular stress, altered synaptic plasticity and mitochondrial function, but not inflammation. Changes in N42 cells show an effect of PA but not OA on DRP-2 and on mitochondrial morphology indicating that long-chain saturated fatty acids damage neuronal function.
| Original language | English |
|---|---|
| Article number | 26 |
| Journal | Nutrition and Metabolism |
| Volume | 16 |
| DOIs | |
| Publication status | Published - 29 Apr 2019 |
Bibliographical note
FundingLMW, FMC, CG, ACM and C-DM were funded by the Scottish Government’s Rural and Environment Science and Analytical Services Division (RESAS). FHM was supported by an EASTBIO DTP BBSRC studentship. DS was supported by a SULSA studentship. CR was supported by the HOTSTART Scholarship Programme from the School of Medicine, Medical Sciences and Nutrition, University of Aberdeen.
Availability of data and materials
All data generated or analysed during this study are included in this published article [and its Supplementary information files].
Keywords
- Hypothalamus
- Proteomics
- Mice
- High-fat diet
- Neuronal plasticity
- ALZHEIMERS-DISEASE
- ER STRESS
- IMPAIRED GLUCOSE-TOLERANCE
- DENDRITIC SPINES
- ORGANIZATION
- OBESITY
- INSULIN-RESISTANCE
- GROWTH
- LEPTIN RESISTANCE
- BRAIN
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- A high-fat diet induces rapid changes in the mouse hypothalamic proteome
© The Author(s). 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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Fiona Campbell
- School of Medicine, Medical Sciences & Nutrition, The Rowett Institute of Nutrition and Health - Research Fellow
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