Biology subjects

Shum, M.

Publications and source records attributed to Shum, M..

5 recordsLinked to original sources

bioRxiv2026

Dietary protein source dictates the impact of obesogenic diets on hepatic steatosis and insulin resistance via carnitine-dependent regulation of acetyl-CoA carboxylase

Nutritional strategies to mitigate obesity and type 2 diabetes (T2D) have largely focused on dietary fat and carbohydrate composition, with less attention given to protein sources. While total dietary protein intake is recognized as an important modulator of energy balance and glucose metabolism, it remains unclear how the composition of dietary proteins can influence energy metabolism and body weight gain. Here, we investigated the metabolic effects of three distinct protein sources from meat (pork), dairy (casein) and plant (soy) on either a low-fat low sucrose (LFLS) or a high-fat high sucrose (HFHS) diet. While protein sources failed to influence metabolic homeostasis on LFLS, mice kept on the HFHS diet were distinctly impacted by the dietary protein sources. Pork and to a lesser extent soy protein feeding exacerbated obesity, glucose intolerance, and hepatic insulin resistance. Remarkably, livers of mice fed pork or soy protein on the HFHS diet were characterized by extensive microvesicular steatosis compared to the predominant macrovesicular steatosis in HFHS fed mice fed casein protein. Liver transcriptomic and metabolomic signatures in pork and soy protein fed mice were consistent with increased mitochondrial beta-oxidation. Intake of pork and soy proteins in HFHS fed mice lead to a striking reduction in hepatic acetyl CoA carboxylase 2 (ACC2) protein levels relative to casein fed HFHS mice. Pork and soy feeding raised carnitine exposure in the post-prandial period and we determined that exposure of hepatocytes to carnitine provokes downregulation of ACC2 and hepatic insulin resistance in the presence of palmitate:oleate and fructose. Collectively, these findings identify a novel mechanism by which dietary proteins modulate obesity and associated metabolic disturbances through a carnitine-mediated regulation of ACC2 protein and mitochondrial lipid handling in liver. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/732886v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@1cc5b9corg.highwire.dtl.DTLVardef@1929e43org.highwire.dtl.DTLVardef@d453faorg.highwire.dtl.DTLVardef@1d56149_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

A cold-inducible phospholipid--protein interaction in brown fat mitochondria optimizes thermogenic capacity

Cold stress elicits dynamic remodeling of the mitochondrial lipidome in brown adipose tissue (BAT), marked by an increase in arachidonoyl-phosphatidylethanolamine (AA-PE). However, the function of membrane lipid rewiring in thermoregulatory physiology has been a longstanding mystery. Here, we identify LPCAT3 as a cold-regulated O-acyltransferase driving the highly selective accrual of AA-PE in BAT mitochondria. Lipid-based proteomics, molecular dynamics simulations, and bioenergetic analyses reveal that AA-PE partitions at the COX4I1 interface of the Cytochrome c oxidase complex, enhancing electron transport chain (ETC) efficiency. Accordingly, fat-specific Lpcat3-knockout mice have defects in respiratory-dependent BAT thermogenesis and cold tolerance, despite intact {beta}-adrenergic signaling and UCP1 function. Under cold acclimation, Lpcat3-/-BAT exhibits ETC dysfunction and activation of the integrated stress-response. Thus, our study illuminates a cold-regulated lipid-protein interaction as a gating factor in UCP1-dependent thermogenesis.

physiology↗

bioRxiv2022

Robust expansion of phylogeny for fast-growing genome sequence data

Massive sequencing of SARS-CoV-2 genomes has led to a great demand for adding new samples to a reference phylogeny instead of building the tree from scratch. To address such challenge, we proposed an algorithm TIPars by integrating parsimony analysis with pre-computed ancestral sequences. Compared to four state-of-the-art methods on four benchmark datasets (SARS-CoV-2, Influenza virus, Newcastle disease virus and 16S rRNA genes), TIPars achieved the best performance in most tests. It took only 21 seconds to insert 100 SARS-CoV-2 genomes to a 100k-taxa reference tree using near 1.4 gigabytes of memory. Its efficient and accurate phylogenetic placements and incrementation for phylogenies with highly similar and divergent sequences suggest that it will be useful in a wide range of studies including pathogen molecular epidemiology, microbiome diversity and systematics.

bioinformatics↗

bioRxiv2019

Single cell profiling of the VMH reveals a sexually dimorphic regulatory node of energy expenditure

Estrogen signaling in the central nervous system promotes weight loss by increasing thermogenesis and physical activity in the ventromedial hypothalamus (VMH), but the precise neuronal populations regulating these aspects of energy expenditure remain unclear. Here we define the molecular and functional heterogeneity of the VMH using single cell RNA sequencing, in situ hybridization, chemogenetic activation, and targeted gene knockdown. We describe six molecularly distinct neuron clusters in the VMH. In females, estrogen receptor alpha (ER) is restricted to neurons expressing tachykinin-1 (Tac1) or reprimo (Rprm). Further, Tac1 and Rprm expression is enriched in females, a sex difference that is established by permanent effects of gonadal hormones early in life. Finally, while Tac1 ablation selectively impairs movement, here we show that silencing Rprm selectively dysregulates temperature without affecting physical activity. Together this work provides a novel architectural framework whereby distinct and sexually differentiated neuron populations within the VMH mediate sex-specific aspects of metabolic homeostasis.

neuroscience↗

bioRxiv2018

NCLX prevents cell death during adrenergic activation of the brown adipose tissue

A sharp increase in mitochondrial Ca2+ marks the activation of the brown adipose tissue (BAT) thermogenesis, yet the mechanisms preventing Ca2+ deleterious effects are poorly understood. Here, we show that adrenergic stimulation of BAT activates a PKA-dependent mitochondrial Ca2+ extrusion via the mitochondrial Na+/Ca2+ exchanger, NCLX. Adrenergic stimulation of NCLX-ablated brown adipocytes (BA) induces a profound mitochondrial Ca2+ overload and impaired uncoupled respiration. Core body temperature, PET imaging and VO2 measurements confirm a BAT specific thermogenic defect in NCLX-null mice.\n\nWe show that mitochondrial Ca2+ overload induced by adrenergic stimulation of NCLX-null BAT, triggers the opening of the mitochondrial permeability transition pore (mPTP), leading to remarkable mitochondrial swelling, Cytochrome c release and cell death in BAT. However, treatment with mPTP inhibitors rescue mitochondrial respiratory function and thermogenesis in NCLX-null BA, in vitro and in vivo.\n\nOur findings identify a novel pathway enabling non-lethal mitochondrial Ca2+ elevation during adrenergic stimulation of uncoupled respiration. Deletion of NCLX transforms the adrenergic pathway responsible for the stimulation of thermogenesis into a death pathway.

physiology↗