Effect of Cpt1a deletion in the mediobasal hypothalamus in response to physical activity and aging
[eng] Food intake and energy homeostasis are tightly regulated by the brain through a complex neuronal network located in the hypothalamus. Within this region, the mediobasal hypothalamus (MBH) acts as an interface between metabolic signals and neuroendocrine pathways governing energy balance in the...
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| Format: | doctoral thesis |
| Status: | Published version |
| Publication Date: | 2022 |
| Country: | España |
| Institution: | Universidad de Barcelona |
| Repository: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/192710 |
| Online Access: | https://hdl.handle.net/2445/192710 http://hdl.handle.net/10803/687536 |
| Access Level: | Open access |
| Keyword: | Metabolisme energètic Carnitina palmitoïl-transferasa 1 Envelliment Múscul estriat Hipotàlem Energy metabolism Carnitine palmitoyltransferase I Aging Striated muscle Hypothalamus |
| Summary: | [eng] Food intake and energy homeostasis are tightly regulated by the brain through a complex neuronal network located in the hypothalamus. Within this region, the mediobasal hypothalamus (MBH) acts as an interface between metabolic signals and neuroendocrine pathways governing energy balance in the central nervous system. The MBH includes two hypothalamic nuclei involved in energy balance: the ventromedial nucleus (VMN) and the arcuate nucleus (ARC). In the VMN, steroidogenic factor 1 (SF1) neurons play a critical role in the feeding and energy control. In addition, agouti-related protein (AgRP) neurons in the ARC participate in the regulation of food intake and energy expenditure. Lipid metabolism in the MBH can modulate the whole-body energy balance. However, how changes in this pathway influence specific neuronal activity remains unclear. Carnitine palmitoyltransferase 1a (Cpt1a), which regulates the rate-limiting step in the mitochondrial fatty acid oxidation, is one of key enzymes involved in this regulation. In this work, we have analysed (1) the metabolic phenotype of mice lacking specifically Cpt1a in SF1 neurons (SF1 Cpt1a KO), and (2) the effect of Cpt1a in AgRP neurons on exercise and cognition using a mutant mouse model lacking Cpt1a in AgRP neurons (AgRP Cpt1a KO) in adult and aged mice. Our results demonstrate that both male and female SF1 Cpt1a KO mice show a mild reduction in food intake without affecting body weight. Moreover, only female SF1 Cpt1a KO mice exhibit enhanced brown adipose tissue (BAT) activity, while this is not observed in SF1 Cpt1a KO male mice. Under high fat diet (HFD) conditions, male SF1 Cpt1a KO mice lost completely this moderate feeding phenotype. Because of that phenotype, we did not continue with these studies. Exercise, the main component of energy expenditure, has a powerful action on metabolism. Specifically, in the skeletal muscle, exercise induces signalling pathways that modify the metabolism and physiological properties of muscle fibres. Regular exercise is strongly associated with increased lifespan and decreased risk of metabolic and mental disorders during aging. In the present study, we have evaluated the physical and cognitive abilities of AgRP Cpt1a KO mice. Adult AgRP Cpt1a KO mice exhibit an improvement in endurance, motor coordination, locomotion, and exploration, without changes in anxiety-related behaviour, cognition, and strength. AgRP Cpt1a KO mice also show a reduction in muscle mass related to a smaller cross-sectional area (CSA) and myofibre transition from glycolytic to oxidative fibres in the gastrocnemius (GAS) and tibialis anterior (TA) muscles compared to the control group. This improvement in physical performance and muscle fibres remodelling are maintained in aged AgRP Cpt1a KO mice, minimising the loss of physical capacity during aging. In addition, aged AgRP Cpt1a KO mice displayed better cognition skills and a reduction of inflammation and oxidative stress in the hypothalamus and the hippocampus. At a central level, the deletion of Cpt1a in AgRP neurons from adult ZsGreen mice alters mitochondrial motility. At a cellular level, the molecular effect produced by the silencing of Cpt1a were tested by two different non-coding RNAs in two AgRP hypothalamic cell lines (mHypoE-41 and E-46). Our results revealed that miRNA 6540-5p has a potential role in inhibiting Cpt1a gene expression. Future studies will allow us to understand the mechanisms implicated in this modulation in response to exercise and aging. In conclusion, Cpt1a in AgRP neurons results essential to modulate exercise performance, myofibre remodelling and cognition. Nonetheless, future studies are needed to clarify the specific role of Cpt1a as a potential anti-aging candidate for the treatment of a wide-diversity disorders, where memory or physical activity are affected such as obesity, Parkinson’s, and Alzheimer’s diseases. |
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