Biology subjects

Alcaide-Corral, C. J.

Publications and source records attributed to Alcaide-Corral, C. J..

3 recordsLinked to original sources

bioRxiv2022

In vivo 18F-DOPA PET imaging identifies a dopaminergic deficit in a rat model with a G51D α-synuclein mutation

Parkinsons disease (PD) is a neurodegenerative condition with several major hallmarks, including loss of substantia nigra neurons, reduction in striatal dopaminergic function, and formation of -synuclein-rich Lewy bodies. Mutations in SNCA, encoding for -synuclein, are a known cause of familial PD, and the G51D mutation causes a particularly aggressive form of the condition. CRISPR/Cas9 technology was used to introduce the G51D mutation into the endogenous rat SNCA gene. SNCAG51D/+ and SNCAG51D/G51D rats were born in Mendelian ratios and did not exhibit any severe behavourial defects. L-3,4-dihydroxy-6-18F-fluorophenylalanine (18F-DOPA) positron emission tomography (PET) imaging was used to investigate this novel rat model. Wild-type (WT), SNCAG51D/+ and SNCAG51D/G51D rats were characterised over the course of ageing (5, 11, and 16 months old) using 18F-DOPA PET imaging and kinetic modelling. We measured the influx rate constant (Ki) and effective distribution volume ratio (EDVR) of 18F-DOPA in the striatum relative to the cerebellum in WT, SNCAG51D/+ and SNCAG51D/G51D rats. A significant reduction in EDVR was observed in SNCAG51D/G51D rats at 16 months of age indicative of increased dopamine turnover. Furthermore, we observed a significant asymmetry in EDVR between the left and right striatum in aged SNCAG51D/G51D rats. The increased and asymmetric dopamine turnover observed in the striatum of aged SNCAG51D/G51D rats is similar to prodromal PD, which suggests the presence of compensatory mechanisms. SNCAG51D rats represent a novel genetic model of PD, and kinetic modelling of 18F-DOPA PET data has identified a highly relevant early disease phenotype.

neuroscience↗

bioRxiv2022

The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent

Caloric restriction (CR) is a nutritional intervention that reduces the risk of age-related diseases in numerous species, including humans. CRs metabolic effects, including decreased fat mass and improved insulin sensitivity, play an important role in its broader health benefits. However, the extent and basis of sex differences in CRs health benefits are unknown. We found that 30% CR in young (3-month-old) male mice decreased fat mass and improved glucose tolerance and insulin sensitivity, whereas these effects were blunted or absent in young female mice. Females resistance to fat and weight loss was associated with decreased lipolysis, lower systemic energy expenditure and fatty acid oxidation, and increased postprandial lipogenesis compared to males. Positron emission tomography-computed tomography (PET/CT) with 18F-fluorodeoxyglucose (18F-FDG) showed that peripheral glucose uptake was comparable between sexes. Instead, the sex differences in glucose homeostasis were associated with altered hepatic ceramide content and substrate metabolism: compared to CR males, CR females had lower TCA cycle activity but higher blood ketone concentrations, a marker of hepatic acetyl-CoA content. This suggests that males use hepatic acetyl-CoA for the TCA cycle whereas in females it accumulates, thereby stimulating gluconeogenesis and limiting hypoglycaemia during CR. In aged mice (18-months old), when females are anoestrus, CR decreased fat mass and improved glucose homeostasis to a similar extent in both sexes. Finally, in a cohort of overweight and obese humans CR-induced fat loss was also sex- and age-dependent: younger females (<45 years) resisted fat loss compared to younger males while in older subjects (>45 years) this sex difference was absent. Collectively, these studies identify age-dependent sex differences in the metabolic effects of CR and highlight adipose tissue, the liver and oestrogen as key determinants of CRs metabolic benefits. These findings have important implications for understanding the interplay between diet and health and for maximising the benefits of CR in humans. HIGHLIGHTSO_LICaloric restriction (CR) decreases fat mass and improves glucose homeostasis in young male mice, but young females resist these effects. C_LIO_LICR females resist lipolysis, decrease energy expenditure and increase postprandial lipogenesis more than CR males, explaining how females resist fat loss. C_LIO_LISex differences in glucose homeostasis are associated with altered hepatic metabolism and gluconeogenesis, without marked differences in peripheral glucose uptake. C_LIO_LICRs effects on fat loss and glucose homeostasis are comparable in aged male and female mice, implicating oestrogen as the driver of the sexually dimorphic effects in young mice. C_LIO_LIIn humans, females resist CR-induced fat loss in an age-dependent manner, further supporting the role of oestrogen in the sexually dimorphic effects of CR. C_LI

physiology↗

bioRxiv2021

A systems-level analysis of dynamic total-body PET data reveals complex skeletal energy metabolism networks in vivo

Bone is now regarded to be a key regulator of a number of metabolic processes, in addition to the regulation of mineral metabolism. However, our understanding of complex bone metabolic interactions at a systems level remains rudimentary, limiting our ability to assess systemic mechanisms underlying diseases and develop novel therapeutics. In vitro molecular biology and bioinformatics approaches have frequently been used to understand the mechanistic changes underlying disease at the cell level, however, these approaches lack the capability to interrogate dynamic multi-bone metabolic interactions in vivo. Here we present a novel and integrative approach to understand complex bone metabolic interactions in vivo using total-body positron emission tomography (PET) network analysis of murine 18F-FDG scans, as a biomarker of glucose metabolism signature in bones. In this report we show that different bones within the skeleton have a unique glucose metabolism and form a complex metabolic network. These data could have important therapeutic implications in the management of the metabolic syndrome and skeletal disease. The application of our approach to clinical and preclinical total-body PET studies promises to reveal further physiological and pathological tissue interactions, which simplistic PET standard uptake values analysis fail to interrogate, extending beyond skeletal metabolism, due to the diversity of PET radiotracers available and under development as well as the advent of clinical total-body PET systems. One Sentence SummaryBones form a complex metabolic network.

physiology↗