A high-fat diet induces rapid changes in the mouse hypothalamic proteome

Fiona H. McLean, Fiona M. Campbell, Rosamund F. Langston, Domenico Sergi, Cibell Resch, Christine Grant, Amanda Morris, Claus-Dieter Mayer, Lynda M. Williams (Corresponding Author)

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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.
Original languageEnglish
Article number26
JournalNutrition and Metabolism
Volume16
DOIs
Publication statusPublished - 29 Apr 2019

Fingerprint

High Fat Diet
Proteome
Palmitic Acid
Oleic Acid
Neuronal Plasticity
Proteomics
Proteins
Fatty Acids
Inflammation
Glucose
Fat-Restricted Diet
Microtubule-Associated Proteins
Glucose Intolerance
Adiposity
Glucose Tolerance Test
Cytoskeleton
Microtubules
Hypothalamus
Insulin Resistance
Alzheimer Disease

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

ASJC Scopus subject areas

  • Nutrition and Dietetics
  • Medicine (miscellaneous)
  • Endocrinology, Diabetes and Metabolism

Cite this

A high-fat diet induces rapid changes in the mouse hypothalamic proteome. / McLean, Fiona H.; Campbell, Fiona M.; Langston, Rosamund F.; Sergi, Domenico; Resch, Cibell; Grant, Christine; Morris, Amanda; Mayer, Claus-Dieter; Williams, Lynda M. (Corresponding Author).

In: Nutrition and Metabolism, Vol. 16, 26, 29.04.2019.

Research output: Contribution to journalArticle

McLean, Fiona H. ; Campbell, Fiona M. ; Langston, Rosamund F. ; Sergi, Domenico ; Resch, Cibell ; Grant, Christine ; Morris, Amanda ; Mayer, Claus-Dieter ; Williams, Lynda M. / A high-fat diet induces rapid changes in the mouse hypothalamic proteome. In: Nutrition and Metabolism. 2019 ; Vol. 16.
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abstract = "BackgroundProlonged 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.MethodsMice 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).ResultsMice 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.ConclusionThese 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.",
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",
author = "McLean, {Fiona H.} and Campbell, {Fiona M.} and Langston, {Rosamund F.} and Domenico Sergi and Cibell Resch and Christine Grant and Amanda Morris and Claus-Dieter Mayer and Williams, {Lynda M.}",
note = "Funding LMW, 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].",
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TY - JOUR

T1 - A high-fat diet induces rapid changes in the mouse hypothalamic proteome

AU - McLean, Fiona H.

AU - Campbell, Fiona M.

AU - Langston, Rosamund F.

AU - Sergi, Domenico

AU - Resch, Cibell

AU - Grant, Christine

AU - Morris, Amanda

AU - Mayer, Claus-Dieter

AU - Williams, Lynda M.

N1 - Funding LMW, 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].

PY - 2019/4/29

Y1 - 2019/4/29

N2 - BackgroundProlonged 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.MethodsMice 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).ResultsMice 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.ConclusionThese 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.

AB - BackgroundProlonged 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.MethodsMice 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).ResultsMice 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.ConclusionThese 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.

KW - Hypothalamus

KW - Proteomics

KW - Mice

KW - High-fat diet

KW - Neuronal plasticity

KW - ALZHEIMERS-DISEASE

KW - ER STRESS

KW - IMPAIRED GLUCOSE-TOLERANCE

KW - DENDRITIC SPINES

KW - ORGANIZATION

KW - OBESITY

KW - INSULIN-RESISTANCE

KW - GROWTH

KW - LEPTIN RESISTANCE

KW - BRAIN

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