Anatomy and Neuroscience - Research Publications
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ItemNo Preview AvailableTwo regulatory T cell populations in the visceral adipose tissue shape systemic metabolism(NATURE PORTFOLIO, 2024-03)Visceral adipose tissue (VAT) is an energy store and endocrine organ critical for metabolic homeostasis. Regulatory T (Treg) cells restrain inflammation to preserve VAT homeostasis and glucose tolerance. Here, we show that the VAT harbors two distinct Treg cell populations: prototypical serum stimulation 2-positive (ST2+) Treg cells that are enriched in males and a previously uncharacterized population of C-X-C motif chemokine receptor 3-positive (CXCR3+) Treg cells that are enriched in females. We show that the transcription factors GATA-binding protein 3 and peroxisome proliferator-activated receptor-γ, together with the cytokine interleukin-33, promote the differentiation of ST2+ VAT Treg cells but repress CXCR3+ Treg cells. Conversely, the differentiation of CXCR3+ Treg cells is mediated by the cytokine interferon-γ and the transcription factor T-bet, which also antagonize ST2+ Treg cells. Finally, we demonstrate that ST2+ Treg cells preserve glucose homeostasis, whereas CXCR3+ Treg cells restrain inflammation in lean VAT and prevent glucose intolerance under high-fat diet conditions. Overall, this study defines two molecularly and developmentally distinct VAT Treg cell types with unique context- and sex-specific functions.
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ItemLiver-derived extracellular vesicles improve whole-body glycaemic control via inter-organ communication(NATURE PORTFOLIO, 2024-02)Small extracellular vesicles (EVs) are signalling messengers that regulate inter-tissue communication through delivery of their molecular cargo. Here, we show that liver-derived EVs are acute regulators of whole-body glycaemic control in mice. Liver EV secretion into the circulation is increased in response to hyperglycaemia, resulting in increased glucose effectiveness and insulin secretion through direct inter-organ EV signalling to skeletal muscle and the pancreas, respectively. This acute blood glucose lowering effect occurs in healthy and obese mice with non-alcoholic fatty liver disease, despite marked remodelling of the liver-derived EV proteome in obese mice. The EV-mediated blood glucose lowering effects were recapitulated by administration of liver EVs derived from humans with or without progressive non-alcoholic fatty liver disease, suggesting broad functional conservation of liver EV signalling and potential therapeutic utility. Taken together, this work reveals a mechanism whereby liver EVs act on peripheral tissues via endocrine signalling to restore euglycaemia in the postprandial state.
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ItemNo Preview AvailableIntestinal-specific Hdac3 deletion increases susceptibility to colitis and small intestinal tumor development in mice fed a high-fat diet(American Physiological Society, 2023-12-03)High-fat (HF) diets (HFDs) and inflammation are risk factors for colon cancer; however, the underlying mechanisms remain to be fully elucidated. The transcriptional corepressor HDAC3 has recently emerged as a key regulator of intestinal epithelial responses to diet and inflammation with intestinal-specific Hdac3 deletion (Hdac3IKO) in mice increasing fatty acid oxidation genes and the rate of fatty acid oxidation in enterocytes. Hdac3IKO mice are also predisposed to experimentally induced colitis; however, whether this is driven by the intestinal metabolic reprogramming and whether this predisposes these mice to intestinal tumorigenesis is unknown. Herein, we examined the effects of intestinal-specific Hdac3 deletion on colitis-associated intestinal tumorigenesis in mice fed a standard (STD) or HFD. Hdac3IKO mice were highly prone to experimentally induced colitis, which was further enhanced by an HFD. Hdac3 deletion also accelerated intestinal tumor development, specifically when fed an HFD and most notably in the small intestine where lipid absorption is maximal. Expression of proteins involved in fatty acid metabolism and oxidation (SCD1, EHHADH) were elevated in the small intestine of Hdac3IKO mice fed an HFD, and these mice displayed increased levels of lipid peroxidation, DNA damage, and apoptosis in their villi, as well as extensive expansion of the stem cell and progenitor cell compartment. These findings reveal a novel role for Hdac3 in suppressing colitis and intestinal tumorigenesis, particularly in the context of consumption of an HFD, and reveal a potential mechanism by which HFDs may increase intestinal tumorigenesis by increasing fatty acid oxidation, DNA damage, and intestinal epithelial cell turnover.NEW & NOTEWORTHY We reveal a novel role for the transcriptional corepressor Hdac3 in suppressing colitis and intestinal tumorigenesis, particularly in the context of consumption of an HFD, and reveal a potential mechanism by which HFDs may increase intestinal tumorigenesis by increasing fatty acid oxidation, DNA damage, and intestinal epithelial cell turnover. We also identify a unique mouse model for investigating the complex interplay between diet, metabolic reprogramming, and tumor predisposition in the intestinal epithelium.
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ItemExercise training induces depot-specific remodeling of protein secretion in skeletal muscle and adipose tissue of obese male mice(AMER PHYSIOLOGICAL SOC, 2023-09-01)Acute exercise induces changes in circulating proteins, which are known to alter metabolism and systemic energy balance. Skeletal muscle is a primary contributor to changes in the plasma proteome with acute exercise. An important consideration when assessing the endocrine function of muscle is the presence of different fiber types, which show distinct functional and metabolic properties and likely secrete different proteins. Similarly, adipokines are important regulators of systemic metabolism and have been shown to differ between depots. Given the health-promoting effects of exercise, we proposed that understanding depot-specific remodeling of protein secretion in muscle and adipose tissue would provide new insights into intertissue communication and uncover novel regulators of energy homeostasis. Here, we examined the effect of endurance exercise training on protein secretion from fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus muscle and visceral and subcutaneous adipose tissue. High-fat diet-fed mice were exercise trained for 6 wk, whereas a Control group remained sedentary. Secreted proteins from excised EDL and soleus muscle, inguinal, and epididymal adipose tissues were detected using mass spectrometry. We detected 575 and 784 secreted proteins from EDL and soleus muscle and 738 and 920 proteins from inguinal and epididymal adipose tissue, respectively. Of these, 331 proteins were secreted from all tissues, whereas secretion of many other proteins was tissue and depot specific. Exercise training led to substantial remodeling of protein secretion from EDL, whereas soleus showed only minor changes. Myokines released exclusively from EDL or soleus were associated with glycogen metabolism and cellular stress response, respectively. Adipokine secretion was completely refractory to exercise regulation in both adipose depots. This study provides an in-depth resource of protein secretion from muscle and adipose tissue, and its regulation following exercise training, and identifies distinct depot-specific secretion patterns that are related to the metabolic properties of the tissue of origin.NEW & NOTEWORTHY The present study examines the effects of exercise training on protein secretion from fast-twitch and slow-twitch muscle as well as visceral and subcutaneous adipose tissue of obese mice. Although exercise training leads to substantial remodeling of protein secretion from fast-twitch muscle, adipose tissue is completely refractory to exercise regulation.
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ItemHuman visceral and subcutaneous adipose stem and progenitor cells retain depot-specific adipogenic properties during obesity(FRONTIERS MEDIA SA, 2022-10-17)Abdominal obesity associates with cardiometabolic disease and an accumulation of lipids in the visceral adipose depot, whereas lipid accumulation in the subcutaneous depot is more benign. We aimed to further investigate whether the adipogenic properties where cell-intrinsic, or dependent on a depot-specific or obesity-produced microenvironment. We obtained visceral and subcutaneous biopsies from non-obese women (n = 14) or women living with morbid obesity (n = 14) and isolated adipose stem and progenitor cells (ASPCs) from the stromal vascular fraction of non-obese (n = 13) and obese (n = 13). Following in vitro differentiation into mature adipocytes, we observed a contrasting pattern with a lower gene expression of adipogenic markers and a higher gene expression of immunogenic markers in the visceral compared to the subcutaneous adipocytes. We identified the immunogenic factor BST2 as a marker for visceral ASPCs. The effect of obesity and insulin resistance on adipogenic and immunogenic markers in the in vitro differentiated cells was minor. In contrast, differentiation with exogenous Tumor necrosis factor resulted in increased immunogenic signatures, including increased expression of BST2, and decreased adipogenic signatures in cells from both depots. Our data, from 26 women, underscore the intrinsic differences between human visceral and subcutaneous adipose stem and progenitor cells, suggest that dysregulation of adipocytes in obesity mainly occurs at a post-progenitor stage, and highlight an inflammatory microenvironment as a major constraint of human adipogenesis.
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ItemLipid droplets and ferroptosis as new players in brain cancer glioblastoma progression and therapeutic resistance(FRONTIERS MEDIA SA, 2022-12-15)A primary brain tumor glioblastoma is the most lethal of all cancers and remains an extremely challenging disease. Apparent oncogenic signaling in glioblastoma is genetically complex and raised at any stage of the disease's progression. Many clinical trials have shown that anticancer drugs for any specific oncogene aberrantly expressed in glioblastoma show very limited activity. Recent discoveries have highlighted that alterations in tumor metabolism also contribute to disease progression and resistance to current therapeutics for glioblastoma, implicating an alternative avenue to improve outcomes in glioblastoma patients. The roles of glucose, glutamine and tryptophan metabolism in glioblastoma pathogenesis have previously been described. This article provides an overview of the metabolic network and regulatory changes associated with lipid droplets that suppress ferroptosis. Ferroptosis is a newly discovered type of nonapoptotic programmed cell death induced by excessive lipid peroxidation. Although few studies have focused on potential correlations between tumor progression and lipid droplet abundance, there has recently been increasing interest in identifying key players in lipid droplet biology that suppress ferroptosis and whether these dependencies can be effectively exploited in cancer treatment. This article discusses how lipid droplet metabolism, including lipid synthesis, storage, and use modulates ferroptosis sensitivity or tolerance in different cancer models, focusing on glioblastoma.
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ItemNo Preview AvailableLiver-Secreted Hexosaminidase A Regulates Insulin-Like Growth Factor Signaling and Glucose Transport in Skeletal Muscle(AMER DIABETES ASSOC, 2023-06)Nonalcoholic fatty liver disease (NAFLD) and impaired glycemic control are closely linked; however, the pathophysiological mechanisms underpinning this bidirectional relationship remain unresolved. The high secretory capacity of the liver and impairments in protein secretion in NAFLD suggest that endocrine changes in the liver are likely to contribute to glycemic defects. We identify hexosaminidase A (HEXA) as an NAFLD-induced hepatokine in both mice and humans. HEXA regulates sphingolipid metabolism, converting GM2 to GM3 gangliosides-sphingolipids that are primarily localized to cell-surface lipid rafts. Using recombinant murine HEXA protein, an enzymatically inactive HEXA(R178H) mutant, or adeno-associated virus vectors to induce hepatocyte-specific overexpression of HEXA, we show that HEXA improves blood glucose control by increasing skeletal muscle glucose uptake in mouse models of insulin resistance and type 2 diabetes, with these effects being dependent on HEXA's enzymatic action. Mechanistically, HEXA remodels muscle lipid raft ganglioside composition, thereby increasing IGF-1 signaling and GLUT4 localization to the cell surface. Disrupting lipid rafts reverses these HEXA-mediated effects. In this study, we identify a pathway for intertissue communication between liver and skeletal muscle in the regulation of systemic glycemic control.
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ItemNo Preview AvailableInvestigating dual inhibition of ACC and CD36 for the treatment of nonalcoholic fatty liver disease in mice(AMER PHYSIOLOGICAL SOC, 2023-02)Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Dysregulation in hepatic lipid metabolism, including increased fatty acid uptake and de novo lipogenesis (DNL), is a hallmark of NAFLD. Here, we investigated dual inhibition of the fatty acid transporter fatty acid translocase (FAT/CD36), and acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in DNL, for the treatment of NAFLD in mice. Mice with hepatic CD36 deletion (Cd36LKO) and wild-type littermates were fed a high-fat diet for 12 wk and treated daily with either oral administration of an ACC inhibitor (GS-834356, Gilead Sciences; ACCi) or vehicle for 8 wk. Neither CD36 deletion or ACC inhibition impacted body composition, energy expenditure, or glucose tolerance. Cd36LKO mice had elevated fasting plasma insulin, suggesting mild insulin resistance. Whole body fatty acid oxidation was significantly decreased in Cd36LKO mice. Liver triglyceride content was significantly reduced in mice treated with ACCi; however, CD36 deletion caused an unexpected increase in liver triglycerides. This was associated with upregulation of genes and proteins of DNL, including ACC, and decreased liver triglyceride secretion ex vivo. Overall, these data confirm the therapeutic utility of ACC inhibition for steatosis resolution but indicate that inhibition of CD36 is not an effective treatment for NAFLD in mice.NEW & NOTEWORTHY Dysregulation of hepatic lipid metabolism is a hallmark of nonalcoholic fatty liver disease. Here, we show that dual inhibition of the de novo lipogenesis enzyme, ACC, and hepatic deletion of the fatty acid transporter, CD36, was ineffective for the treatment of NAFLD in mice. This was due to a paradoxical increase in liver triglycerides with CD36 deletion resulting from decreased hepatic triglyceride secretion and increased lipogenic gene expression.
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ItemNo Preview AvailableMulti-substrate Metabolic Tracing Reveals Marked Heterogeneity and Dependency on Fatty Acid Metabolism in Human Prostate Cancer(AMER ASSOC CANCER RESEARCH, 2023-04)UNLABELLED: Cancer cells undergo metabolic reprogramming to meet increased bioenergetic demands. Studies in cells and mice have highlighted the importance of oxidative metabolism and lipogenesis in prostate cancer; however, the metabolic landscape of human prostate cancer remains unclear. To address this knowledge gap, we performed radiometric (14C) and stable (13C) isotope tracing assays in precision-cut slices of patient-derived xenografts (PDX). Glucose, glutamine, and fatty acid oxidation was variably upregulated in malignant PDXs compared with benign PDXs. De novo lipogenesis (DNL) and storage of free fatty acids into phospholipids and triacylglycerols were increased in malignant PDXs. There was no difference in substrate utilization between localized and metastatic PDXs and hierarchical clustering revealed marked metabolic heterogeneity across all PDXs. Mechanistically, glucose utilization was mediated by acetyl-CoA production rather than carboxylation of pyruvate, while glutamine entered the tricarboxylic acid cycle through transaminase reactions before being utilized via oxidative or reductive pathways. Blocking fatty acid uptake or fatty acid oxidation with pharmacologic inhibitors was sufficient to reduce cell viability in PDX-derived organoids, whereas blockade of DNL, or glucose or glutamine oxidation induced variable and limited therapeutic efficacy. These findings demonstrate that human prostate cancer, irrespective of disease stage, can effectively utilize all metabolic substrates, albeit with marked heterogeneity across tumors. We also confirm that fatty acid uptake and oxidation are targetable metabolic dependencies in human prostate cancer. IMPLICATIONS: Prostate cancer utilizes multiple substrates to fuel energy requirements, yet pharmacologic targeting of fatty acid uptake and oxidation reveals metabolic dependencies in localized and metastatic tumors.
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ItemNo Preview AvailablePhosphoproteomics of three exercise modalities identifies canonical signaling and C18ORF25 as anAMPK substrate regulating skeletal muscle function(CELL PRESS, 2022-10-04)Exercise induces signaling networks to improve muscle function and confer health benefits. To identify divergent and common signaling networks during and after different exercise modalities, we performed a phosphoproteomic analysis of human skeletal muscle from a cross-over intervention of endurance, sprint, and resistance exercise. This identified 5,486 phosphosites regulated during or after at least one type of exercise modality and only 420 core phosphosites common to all exercise. One of these core phosphosites was S67 on the uncharacterized protein C18ORF25, which we validated as an AMPK substrate. Mice lacking C18ORF25 have reduced skeletal muscle fiber size, exercise capacity, and muscle contractile function, and this was associated with reduced phosphorylation of contractile and Ca2+ handling proteins. Expression of C18ORF25 S66/67D phospho-mimetic reversed the decreased muscle force production. This work defines the divergent and canonical exercise phosphoproteome across different modalities and identifies C18ORF25 as a regulator of exercise signaling and muscle function.