Biology subjects

Rowley, C.

Publications and source records attributed to Rowley, C..

3 recordsLinked to original sources

bioRxiv2023

Profiling human hypothalamic neurons reveals a candidate combination drug therapy for weight loss

Obesity substantially increases the risk of type 2 diabetes, cardiovascular disease, and other diseases, making it a leading preventable cause of death in developed countries. It has a strong genetic basis, with obesity-associated genetic variants preferentially acting in the brain. This includes the hypothalamic pro-opiomelanocortin (POMC) neurons that inhibit food intake and are stimulated by drugs that agonise glucagon-like 1 peptide receptor (GLP1R) including Semaglutide (Ozempic/Wegovy). We therefore hypothesised that drugs which selectively activate human POMC neurons would suppress appetite and promote weight loss, and that focusing on drugs already approved for use would facilitate rapid clinical translation. We therefore generated POMC neurons from human pluripotent stem cells (hPSCs) and identified enriched genes that were genetically associated with obesity and targeted by approved drugs. We found that human POMC neurons are enriched in GLP1R, reliably activated by Semaglutide, and their responses are further increased by co-administration of Ceritinib, an FDA-approved drug potently and selectively inhibiting anaplastic lymphoma kinase (ALK). Ceritinib reduced food intake and body weight in obese but not lean mice, and upregulated the expression of GLP1R in the mouse hypothalamus and hPSC-derived human hypothalamic neurons. These studies reveal a new potential therapeutic strategy for reducing food intake and body weight, and demonstrate the utility of hPSC-derived hypothalamic neurons for drug discovery.

neuroscience↗

bioRxiv2023

Metformin may reduce dementia risk through neuroprotection not mitigation of diabetes

Dementia is a largely untreatable syndrome that is epidemiologically associated with metabolic diseases such as type 2 diabetes (T2D) and obesity. Drugs used to treat T2D such as metformin are inexpensive, safely given to millions of people, and have also been reported to slow neurodegeneration. We hypothesised that the neuroprotective benefits of metformin might extend to metabolically healthy individuals and tested this hypothesis in a mouse prion model that recapitulates key features of human neurodegenerative disease, including synaptic loss and motor impairment. These features and the time course of this model (24 weeks) allows the effects of metabolic risk factors and metformin to be tested and potentially generalised to other forms of neurodegenerative disease. Mice fed a high fat diet (HFD) developed high adiposity with impaired glucose and insulin homeostasis, similar to the effects of chronic obesity seen in humans whereas mice on matched control diet (CD) remain metabolically healthy. Chronic treatment with metformin in HFD-fed mice significantly increased survival and health span relative to vehicle-treated mice. Mice fed a HFD also had a modestly extended health span relative to mice fed CD, as measured by development of motor signs of prion disease. Metformin also significantly extended health span in metabolically healthy CD-fed mice. Using targeted mass spectrometry, we found that metformin reached deep brain structures at functional concentrations, driving a reduction in pPERK and changing the activity of microglia in vivo. Metformin was able to alter ER stress pathways at the same concentrations in healthy animals and using human iPSC-derived microglia and mouse organotypic slices we show that the action of metformin at these concentrations does not require a systemic mechanism, necessary for the treatment of diabetes, and is likely a result of direct secondary pharmacology in the brain. Together, these data broadly support the premise of repurposing metformin for neuroprotection, even in metabolically healthy individuals.

neuroscience↗

bioRxiv2022

Mouse and cellular models of KPTN-related disorder implicate mTOR signalling in cognitive and progressive overgrowth phenotypes

KPTN-related disorder (KRD) is an autosomal recessive disorder associated with germline variants in KPTN (kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KRD, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn-/- mice display many of the key KRD phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. Assessment of affected individuals has identified concordant selectivity of cognitive deficits, postnatal onset of brain overgrowth, and a previously unrecognised KPTN dosage-sensitivity, resulting in increased head circumference in their heterozygous parents. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape, and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated iPSC models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. Increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KRD in the broader group of mTORC1 related disorders affecting brain structure, cognitive function, and network integrity.

genetics↗