Biology subjects

McKay, E. J.

Publications and source records attributed to McKay, E. J..

4 recordsLinked to original sources

bioRxiv2025

Evaluation of Candidate ''Kill or Cure'' Strategies to Treat MFN2-related Lipodystrophy

The R707W mutation in mitofusin 2, encoded by MFN2, causes a form of Multiple Symmetrical Lipomatosis (MFN2-MSL). This resembles sporadic, alcohol-associated MSL, combining loss of lower body adipose tissue with upper body adipose hyperplasia. Morbidity and sometimes mortality arise both from mechanical complications of head and neck adipose overgrowth, and metabolic complications. We reasoned that interventions that either mitigate the underlying cellular pathology, or that exacerbate it to induce selective death of hyperplastic adipose tissue may be beneficial. We thus assessed the effect of a metabolic or pharmacologic stressors or rapamycin in Mfn2R707W/R707W mice and or derived preadipocytes. 50mmol ethanol had little effect on WT or Mfn2R707W/R707W white preadipocytes, but increased mitochondrial content and blunted mitolysosome formation in Mfn2R707W/R707Wbrown preadipocytes. Daily consumption of 20% EtOH increased brown adipose tissue mass in female Mfn2R707W/R707W mice, and serum lactate in males. 200nM rapamycin - a candidate treatment - increased size and mitolysosome content of WT and Mfn2R707W/R707W white and brown preadipocytes, but these effects were blunted in Mfn2R707W/R707W cells. In male but not female Mfn2R707W/R707W mice, rapamycin reduced or reversed weight gain, reduced brown adipose mass, and increased serum Fgf21. Finally, a panel of other metabolic and pharmacological mitochondrial stressors solicited no selective death or ISR in Mfn2R707W/R707W preadipocytes. We conclude that ethanol mildly exacerbates MFN-MSL in mice, while rapamycin is tolerated. Lack of sensitisation to mitochondrial stressors implies that the MSL-inducing effect of MFN2 R707W may not be exerted through compromised oxidative phosphorylation.

physiology↗

bioRxiv2024

The metabolically protective energy expenditure increase of Pik3r1-related insulin resistance is not explained by Ucp1-mediated thermogenesis

Human SHORT syndrome is caused by dominant negative human PIK3R1 mutations that impair insulin-stimulated phosphoinositide 3-kinase (PI3K) activity. This produces severe insulin resistance (IR) and often reduced adiposity, commonly described as lipodystrophy. However unlike human primary lipodystrophies, SHORT syndrome does not feature fatty liver or dyslipidaemia. Pik3r1Y657*/WT (Pik3r1Y657*) mice metabolically phenocopy humans, moreover exhibiting increased energy expenditure. We have hypothesised that this increased energy expenditure explains protection from lipotoxicity, and suggested that understanding its mechanism may offer novel approaches to mitigating the metabolic syndrome. We thus set out to determine whether increased Ucp1-dependent thermogenesis explains the increased energy expenditure in Pik3r1-related IR. Male and female Pik3r1Y657* mice challenged with a 45% fat diet for 3 weeks at 21{degrees}C showed reduced metabolic efficiency not explained by changes in food intake or physical activity. No changes were seen in thermoregulation, assessed by thermal imaging and a modified Scholander protocol. Ucp1-dependent thermogenesis, assessed by norepinephrine-induced oxygen consumption, was also unaltered. Housing at 30{degrees}C did not alter the metabolic phenotype of male Pik3r1Y657* mice, but led to lowered physical activity in female Pik3r1Y657* mice compared to controls. Nevertheless these mice still exhibited increased energy expenditure. Ucp1-dependent thermogenic capacity at 30{degrees}C was similar in Pik3r1Y657* and WT mice. We conclude that the likely metabolically protective energy leak in Pik3r1-related IR is not caused by Ucp1-mediated BAT hyperactivation, nor impaired thermal insulation. Further metabolic studies are required to seek alternative explanations such as non Ucp1-mediated futile cycling. New and NoteworthyUnderstanding how Pik3r1Y657* mice and humans are protected from lipotoxicity despite insulin resistance may suggest new ways to mitigate metabolic syndrome. We find reduced metabolic efficiency and increased energy expenditure in Pik3r1Y657* mice but no differences in locomotion, thermoregulation or Ucp1-dependent thermogenesis. Protective energy expenditure in Pik3r1-related insulin resistance has an alternative, likely metabolic, explanation

physiology↗

bioRxiv2023

Female Alms1-deficient mice develop echocardiographic features of adult but not infantile Alström Syndrome cardiomyopathy

BackgroundAlstrom Syndrome (AS), a multisystem disorder caused by biallelic ALMS1 mutations, features major cardiac complications often causing early mortality. These are biphasic, including infantile dilated cardiomyopathy, and distinct adult-onset cardiomyopathy. Cardiomyocyte maturation defects, cardiac fibrosis and early atherosclerosis have all been invoked as contributors to heart failure in AS, but their relative importance and inter-relationships are unknown. MethodsCardiac function of global Alms1 knockout mice was assessed by echocardiography at postnatal day 15 (P15) and at 8 and 23 weeks of age. Echocardiography was also undertaken in female mice with Pdgfr-Cre-driven Alms1 deletion in cardiac fibroblasts and a small proportion of cardiomyocytes. Histological and transcriptional analysis of myocardium at P15 and 24 weeks of age was also performed. ResultsCardiac function was unaltered in knockout mice of both sexes at P15 and 8 weeks of age. At 23 weeks of age female but not male knockout mice showed increased left atrial area, decreased isovolumic relaxation time, and reduced ejection fraction, consistent with early restrictive cardiomyopathy. No histological or transcriptional changes could be identified in myocardium of 23-week old female Alms1 KO mice, however. Pdgfr-Cre-driven Alms1 KO in females did not recapitulate the phenotype of global KO at 23 weeks. ConclusionsAdult female, but not male, Alms1-deficient mice show echocardiographic evidence of cardiac dysfunction, consistent with the restrictive cardiomyopathy of AS. The explanation for sexual dimorphism remains unclear, but may involve metabolic or endocrine differences between sexes. No infantile cardiomyopathy was found in this study.

physiology↗

bioRxiv2023

Mesenchymal-specific Alms1 knockout in mice recapitulates key metabolic features of Alström Syndrome

BackgroundAlstrom Syndrome (AS), a multi-system disease caused by mutations in the ALMS1 gene, includes obesity with disproportionately severe insulin resistant diabetes, dyslipidemia, and hepatosteatosis. How loss of ALMS1 causes this phenotype is poorly understood, but prior studies have circumstancially implicated impaired adipose tissue expandability. We set out to test this by comparing the metabolic effects of selective Alms1 knockout in mesenchymal cells including preadipocytes to those of global Alms1 knockout. MethodsGlobal Alms1 knockout (KO) mice were generated by crossing floxed Alms1 and CAG-Cre mice. A Pdgfr-Cre driver was used to abrogate Alms1 function selectively in mesenchymal stem cells (MSCs) and their descendants, including preadipocytes. We combined metabolic phenotyping of global and Pdgfr+ Alms1-KO mice on a 45% fat diet with measurements of body composition and food intake, and histological analysis of metabolic tissues. ResultsGlobal Alms1 KO caused hyperphagia, obesity, insulin resistance, dyslipidaemia, and fatty liver. Pdgfr-cre driven KO of Alms1 (MSC KO) recapitulated insulin resistance, fatty liver, and dyslipidaemia in both sexes. Other phenotypes were sexually dimorphic: increased fat mass was only present in female Alms1 MSC KO mice. Hyperphagia was not evident in male Alms1 MSC KO mice, but was found in MSC KO females, despite no neuronal Pdgfr expression. ConclusionsMesenchymal deletion of Alms1 recapitulates the metabolic features of AS, including severe fatty liver. This confirms a key role for Alms1 in the adipose lineage, where its loss is sufficient to cause systemic metabolic effects and damage to remote organs. AS should be regarded as a forme fruste of lipodystrophy. Therapies should prioritise targeting positive energy balance.

physiology↗