Interrogating Amino Acid Metabolism in Metabolic Disorders
BIOENGINEERING SEMINAR
Abstract:
Type 2 Diabetes (T2D) represents a disease spectrum with metabolic dysfunction damaging multiple organ systems including liver, kidneys, and peripheral nerves. Although insulin resistance and dyslipidemia link onset and progression of these co-morbidities, aberrant amino acid metabolism also contributes to pathogenesis of diabetes and potentially its complications. Serine and glycine are closely related non-essential amino acids that are consistently reduced in metabolic syndrome patients, but the mechanistic drivers of serine deficiency and the downstream metabolic and phenotypic consequences remain unclear. Low systemic serine, a serine-opathy, is emerging as a hallmark of retinopathy and peripheral neuropathy, correlating with impaired visual acuity and peripheral neuropathy (PN). Our data demonstrate that aberrant serine homeostasis in the liver drives serine and glycine deficiencies in genetically obese mice. This serine-opathy can be diagnosed with a serine tolerance test that quantifies systemic serine disposal. Mimicking serine deficiency via dietary serine/glycine restriction together with high fat intake dramatically accelerates thermal hypoalgesia in mice and reduces epidermal sensory nerve density, which are accompanied by extensive sciatic nerve lipid remodeling. These phenotypes were subsequently normalized by myriocin, linking serine-associated PN with sphingolipid metabolism. These findings identify systemic serine deficiency and dyslipidemia as novel risk factors for PN that may be exploited therapeutically.
Bio:
Dr. Michal Handzlik trained as a physiotherapist before obtaining a Master's degree in Exercise Physiology (Loughborough University, UK) with Prof. Mike Gleeson and a Ph.D. in Biomedical Sciences (University of Nottingham, UK) with Prof. Paul Greenhaff. Inspired by his diabetic patients, he continued his NIH-supported postdoctoral training with Prof. Christian Metallo (UC San Diego/Salk Institute, US), developing a strong interest in in vivo stable isotope tracing, mass spectrometry, and inter-organ crosstalk to dissect the contribution of aberrant amino acid homeostasis toward the diabetic phenotype and complications.
Zoom link for attending remotely: https://epfl.zoom.us/j/65946248975
Abstract:
Type 2 Diabetes (T2D) represents a disease spectrum with metabolic dysfunction damaging multiple organ systems including liver, kidneys, and peripheral nerves. Although insulin resistance and dyslipidemia link onset and progression of these co-morbidities, aberrant amino acid metabolism also contributes to pathogenesis of diabetes and potentially its complications. Serine and glycine are closely related non-essential amino acids that are consistently reduced in metabolic syndrome patients, but the mechanistic drivers of serine deficiency and the downstream metabolic and phenotypic consequences remain unclear. Low systemic serine, a serine-opathy, is emerging as a hallmark of retinopathy and peripheral neuropathy, correlating with impaired visual acuity and peripheral neuropathy (PN). Our data demonstrate that aberrant serine homeostasis in the liver drives serine and glycine deficiencies in genetically obese mice. This serine-opathy can be diagnosed with a serine tolerance test that quantifies systemic serine disposal. Mimicking serine deficiency via dietary serine/glycine restriction together with high fat intake dramatically accelerates thermal hypoalgesia in mice and reduces epidermal sensory nerve density, which are accompanied by extensive sciatic nerve lipid remodeling. These phenotypes were subsequently normalized by myriocin, linking serine-associated PN with sphingolipid metabolism. These findings identify systemic serine deficiency and dyslipidemia as novel risk factors for PN that may be exploited therapeutically.
Bio:
Dr. Michal Handzlik trained as a physiotherapist before obtaining a Master's degree in Exercise Physiology (Loughborough University, UK) with Prof. Mike Gleeson and a Ph.D. in Biomedical Sciences (University of Nottingham, UK) with Prof. Paul Greenhaff. Inspired by his diabetic patients, he continued his NIH-supported postdoctoral training with Prof. Christian Metallo (UC San Diego/Salk Institute, US), developing a strong interest in in vivo stable isotope tracing, mass spectrometry, and inter-organ crosstalk to dissect the contribution of aberrant amino acid homeostasis toward the diabetic phenotype and complications.
Zoom link for attending remotely: https://epfl.zoom.us/j/65946248975
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