https://orcid.org/0000-0002-9949-5861
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ABSTRACT
Introduction
Lipids regulate a wide range of biological processes. The mechanisms by which fatty acids (FA) and its metabolites influence the hypothalamic regulation of energy homeostasis have been highly studied. However, the effect of ageing and food restriction (FR) on this process is unknown.
Methods
Herein, we analyzed the gene expression, protein and phosphorylation levels of hypothalamic enzymes and transcription factors related to lipid metabolism. Experiments were performed in male Wistar rats of 3-, 8- and 24-month-old Wistar rats fed ad libitum (AL), as ageing model. Besides, 5- and 21-month-old rats were subjected to a moderate FR protocol (equivalent to ≈ 80% of normal food intake) for three months before the sacrifice.
Results
Aged Wistar rats showed a situation of chronic lipid excess as a result of an increase in de novo FA synthesis and FA levels that reach the brain, contributing likely to the development of central leptin and insulin resistance. We observe a hypothalamic downregulation of AMP-activated protein kinase (AMPK) and stearoyl-CoA desaturase (SCD1) and an increase of carnitine palmitoyltransferase-1c (CPT1c) expression.
Discussion
Our results suggest an impairment in the physiological lipid sensing system of aged Wistar rats, which would alter the balance of the intracellular mobilization and trafficking of lipids between the mitochondria and the Endoplasmic Reticulum (ER) in the hypothalamus, leading probably to the development of neurolipotoxicity in aged rats. Lastly, FR can only partially restore this imbalance.
Schematic representation of the fate of LCFA-CoA in the hypothalamus of young and old rats. Blood circulating LCFAs in young Wistar rats reach the hypothalamus, where they are esterified to LCFA-CoA. Into glial cells or neurons, LCFA-CoA are driven to mitochondria (CPT1a) or ER (CPT1c) where could be desaturated by SDC1 and, thereby, converted into structural and signaling unsaturated lipids as oleic acid, related with neuronal myelinization and differentiation. However, the excess of LCFA that reach to the hypothalamus in old animals, could generate an increase in LCFA-CoA, which together with an increase in CPT1c levels, could favor the capture of LCFA-CoA to the ER. The decrease in the levels of SCD1 in old rats would decrease FA unsaturation degree that could trigger lipotoxicity process and neurodegeneration, both related to the development of neurodegenerative diseases linked to age.
GRAPHICAL ABSTRACT
Acknowledgments
María Rodríguez was recipient of a postdoctoral fellowship from BFU2012-39705-C03-01. Torrillas-de la Cal was recipient of a predoctoral fellowship from training program to promote the employment of young researchers from Junta de Comunidades de Castilla-La Mancha (JCCM). The authors thank Sergio Moreno for the excellent technical assistance.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
Notes on contributors
María Rodríguez
María Rodríguez is Assistant Professor in Biochemistry and Molecular Biology. Biochemistry Area. UCLM-CRIB.
Cristina Pintado
Cristina Pintado is Lecturer in Biochemistry and Molecular Biology. Biochemistry Area. UCLM-CRIB.
Rodrigo Torrillas-de la Cal
Rodrigo Torrillas-de la Cal is Graduate in Biochemistry.
Eduardo Moltó
Eduardo Moltó is Reader in Biochemistry and Molecular Biology. Biochemistry Area. UCLM-CRIB.
Nilda Gallardo
Nilda Gallardo is Reader in Biochemistry and Molecular Biology. Biochemistry Area. UCLM-CRIB.
Antonio Andrés
Antonio Andrés is Professor in Biochemistry and Molecular Biology. Biochemistry Area. UCLM-CRIB.
Carmen Arribas
Carmen Arribas is Reader in Biochemistry and Molecular Biology. Biochemistry Area. UCLM-CRIB.