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19 pages, 5219 KiB

Open AccessArticle

Notch Signaling Regulates Mouse Perivascular Adipose Tissue Function via Mitochondrial Pathways

by Chenhao Yang, Xuehui Yang, Anne Harrington, Christian Potts, Abigail Kaija, Larisa Ryzhova and Lucy Liaw

Genes 2023, 14(10), 1964; https://doi.org/10.3390/genes14101964 - 20 Oct 2023

Cited by 1 | Viewed by 1274

Abstract

Perivascular adipose tissue (PVAT) regulates vascular function by secreting vasoactive substances. In mice, Notch signaling is activated in the PVAT during diet-induced obesity, and leads to the loss of the thermogenic phenotype and adipocyte whitening due to increased lipid accumulation. We used the [...] Read more.

Perivascular adipose tissue (PVAT) regulates vascular function by secreting vasoactive substances. In mice, Notch signaling is activated in the PVAT during diet-induced obesity, and leads to the loss of the thermogenic phenotype and adipocyte whitening due to increased lipid accumulation. We used the Adiponectin-Cre (Adipoq-Cre) strain to activate a ligand-independent Notch1 intracellular domain transgene (N1ICD) to drive constitutive Notch signaling in the adipose tissues (N1ICD;Adipoq-Cre). We previously found that constitutive activation of Notch1 signaling in the PVAT phenocopied the effects of diet-induced obesity. To understand the downstream pathways activated by Notch signaling, we performed a proteomic analysis of the PVAT from control versus N1ICD;Adipoq-Cre mice. This comparison identified prominent changes in the protein signatures related to metabolism, adipocyte homeostasis, mitochondrial function, and ferroptosis. PVAT-derived stromal vascular fraction cells were derived from our mouse strains to study the cellular and molecular phenotypes during adipogenic induction. We found that cells with activated Notch signaling displayed decreased mitochondrial respiration despite similar levels of adipogenesis and mitochondrial number. We observed variable regulation of the proteins related to mitochondrial dynamics and ferroptosis, including PHB3, PINK1, pDRP1, and the phospholipid hydroperoxidase GPX4. Mitochondria regulate some forms of ferroptosis, which is a regulated process of cell death driven by lipid peroxidation. Accordingly, we found that Notch activation promoted lipid peroxidation and ferroptosis in PVAT-derived adipocytes. Because the PVAT phenotype is a regulator of vascular reactivity, we tested the effect of Notch activation in PVAT on vasoreactivity using wire myography. The aortae from the N1ICD;Adipoq-Cre mice had increased vasocontraction and decreased vasorelaxation in a PVAT-dependent and age-dependent manner. Our data provide support for the novel concept that increased Notch signaling in the adipose tissue leads to PVAT whitening, impaired mitochondrial function, increased ferroptosis, and loss of a protective vasodilatory signal. Our study advances our understanding of how Notch signaling in adipocytes affects mitochondrial dynamics, which impacts vascular physiology. Full article

(This article belongs to the Special Issue Cellular and Developmental Biology of Lipid Metabolism)

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13 pages, 3929 KiB

Open AccessCommunication

A CRISPR Screen Identifies the E3 Ubiquitin Ligase Rfwd2 as a Negative Regulator of Glucose Uptake in Brown Adipocytes

by Matthew D. Lynes, Qian Huang, Carolina Cora, Sheng-Chiang Su, Peng Yi and Yu-Hua Tseng

Genes 2023, 14(10), 1865; https://doi.org/10.3390/genes14101865 - 26 Sep 2023

Viewed by 1252

Abstract

Brown adipose tissue activation increases energy expenditure and has been shown to improve glucose tolerance, making it a promising target for the treatment of obesity and type 2 diabetes. Brown adipocytes differentiate into cells with multilocular lipid droplets, which can efficiently absorb and [...] Read more.

Brown adipose tissue activation increases energy expenditure and has been shown to improve glucose tolerance, making it a promising target for the treatment of obesity and type 2 diabetes. Brown adipocytes differentiate into cells with multilocular lipid droplets, which can efficiently absorb and oxidize glucose; however, the mechanisms regulating these processes are not completely understood. We conducted a genome-wide loss-of-function screen using a CRISPR-based approach to identify genes that promote or inhibit adipogenesis and glucose uptake in brown adipocytes. We validated genes that negatively or positively regulated these pathways and verified that the E3-ubiquitin ligase Rfwd2 suppressed brown adipocyte glucose uptake. Brown adipocytes with CRISPR-targeted Rfwd2 deletion showed an altered proteomic landscape and increased basal, as well as insulin-stimulated, glucose uptake. These data reveal the complexity of genetic regulation of brown adipogenesis and glucose metabolism. Full article

(This article belongs to the Special Issue Cellular and Developmental Biology of Lipid Metabolism)

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12 pages, 26423 KiB

Open AccessArticle

The Role of Pancreatic Fatty Acid Synthesis in Islet Morphology and Function after Caloric Restriction or Roux-En-Y Gastric Bypass Surgery in Mice

by Haocong Mo, Yang Liu, Mengyuan Zhang, Zirui Qiu, Yilin Li, Zhejiao Zhang, Yanting Li and Geyang Xu

Genes 2023, 14(1), 5; https://doi.org/10.3390/genes14010005 - 20 Dec 2022

Cited by 2 | Viewed by 1406

Abstract

Background: Both caloric restriction (CR) and Roux-en-Y gastric bypass (RYGB) are practical interventions for type 2 diabetes mellitus (T2DM), while the molecular mechanisms of CR and RYGB regarding glycemic control are still poorly understood. Here, we explore the effects and underlying mechanisms of [...] Read more.

Background: Both caloric restriction (CR) and Roux-en-Y gastric bypass (RYGB) are practical interventions for type 2 diabetes mellitus (T2DM), while the molecular mechanisms of CR and RYGB regarding glycemic control are still poorly understood. Here, we explore the effects and underlying mechanisms of CR and RYGB on β-cell area and function. Methods: Average islet size was measured by histological analysis. The pancreatic lipid content was detected by using a commercial lipid assay kit. The expression levels of lipogenic transcription factors and enzymes in mouse pancreas were determined by quantitative PCR, Western blot, and immunofluorescence. Results: CR decreased the mean size of islets and pancreatic insulin production in both regular diet-fed and high-fat diet-fed mice. Increased β-cell apoptosis was detected in the calorie-restricted mice. Interestingly, the lipogenic transcription factors and enzymes such as SREBP1c, PPARγ, FASN and ACC were upregulated in the pancreas after CR. In contrast to CR, RYGB decreased the apoptosis of β-cells and the expression of fatty acid synthase. Conclusions: Pancreatic fatty acid synthesis is critical to the β-cell function after CR and RYGB. Full article

(This article belongs to the Special Issue Cellular and Developmental Biology of Lipid Metabolism)

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Review

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14 pages, 1488 KiB

Open AccessReview

Pericytes as the Orchestrators of Vasculature and Adipogenesis

by Caroline de Carvalho Picoli, Alexander Birbrair and Ziru Li

Genes 2024, 15(1), 126; https://doi.org/10.3390/genes15010126 - 19 Jan 2024

Viewed by 1185

Abstract

Pericytes (PCs) are located surrounding the walls of small blood vessels, particularly capillaries and microvessels. In addition to their functions in maintaining vascular integrity, participating in angiogenesis, and regulating blood flow, PCs also serve as a reservoir for multi-potent stem/progenitor cells in white, [...] Read more.

Pericytes (PCs) are located surrounding the walls of small blood vessels, particularly capillaries and microvessels. In addition to their functions in maintaining vascular integrity, participating in angiogenesis, and regulating blood flow, PCs also serve as a reservoir for multi-potent stem/progenitor cells in white, brown, beige, and bone marrow adipose tissues. Due to the complex nature of this cell population, the identification and characterization of PCs has been challenging. A comprehensive understanding of the heterogeneity of PCs may enhance their potential as therapeutic targets for metabolic syndromes or bone-related diseases. This mini-review summarizes multiple PC markers commonly employed in lineage-tracing studies, with an emphasis on their contribution to adipogenesis and functions in different adipose depots under diverse metabolic conditions. Full article

(This article belongs to the Special Issue Cellular and Developmental Biology of Lipid Metabolism)

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14 pages, 1375 KiB

Open AccessReview

Fatty Acid Metabolism in Endothelial Cell

by Bin Liu and Zhiyu Dai

Genes 2022, 13(12), 2301; https://doi.org/10.3390/genes13122301 - 06 Dec 2022

Cited by 4 | Viewed by 3996

Abstract

The endothelium is a monolayer of cells lining the inner blood vessels. Endothelial cells (ECs) play indispensable roles in angiogenesis, homeostasis, and immune response under normal physiological conditions, and their dysfunction is closely associated with pathologies such as cardiovascular diseases. Abnormal EC metabolism, [...] Read more.

The endothelium is a monolayer of cells lining the inner blood vessels. Endothelial cells (ECs) play indispensable roles in angiogenesis, homeostasis, and immune response under normal physiological conditions, and their dysfunction is closely associated with pathologies such as cardiovascular diseases. Abnormal EC metabolism, especially dysfunctional fatty acid (FA) metabolism, contributes to the development of many diseases including pulmonary hypertension (PH). In this review, we focus on discussing the latest advances in FA metabolism in ECs under normal and pathological conditions with an emphasis on PH. We also highlight areas of research that warrant further investigation. Full article

(This article belongs to the Special Issue Cellular and Developmental Biology of Lipid Metabolism)

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15 pages, 660 KiB

Open AccessReview

Potential Mechanisms of Gut-Derived Extracellular Vesicle Participation in Glucose and Lipid Homeostasis

by Tiange Feng, Weizhen Zhang and Ziru Li

Genes 2022, 13(11), 1964; https://doi.org/10.3390/genes13111964 - 28 Oct 2022

Cited by 2 | Viewed by 2032

Abstract

The intestine participates in the regulation of glucose and lipid metabolism in multiple facets. It is the major site of nutrient digestion and absorption, provides the interface as well as docking locus for gut microbiota, and harbors hormone-producing cells scattered throughout the gut [...] Read more.

The intestine participates in the regulation of glucose and lipid metabolism in multiple facets. It is the major site of nutrient digestion and absorption, provides the interface as well as docking locus for gut microbiota, and harbors hormone-producing cells scattered throughout the gut epithelium. Intestinal extracellular vesicles are known to influence the local immune response, whereas their roles in glucose and lipid homeostasis have barely been explored. Hence, this current review summarizes the latest knowledge of cargo substances detected in intestinal extracellular vesicles, and connects these molecules with the fine-tuning regulation of glucose and lipid metabolism in liver, muscle, pancreas, and adipose tissue. Full article

(This article belongs to the Special Issue Cellular and Developmental Biology of Lipid Metabolism)

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19 pages, 897 KiB

Open AccessReview

Cardiolipin Regulates Mitochondrial Ultrastructure and Function in Mammalian Cells

by Zhitong Jiang, Tao Shen, Helen Huynh, Xi Fang, Zhen Han and Kunfu Ouyang

Genes 2022, 13(10), 1889; https://doi.org/10.3390/genes13101889 - 18 Oct 2022

Cited by 11 | Viewed by 4028

Abstract

Cardiolipin (CL) is a unique, tetra-acylated diphosphatidylglycerol lipid that mainly localizes in the inner mitochondria membrane (IMM) in mammalian cells and plays a central role in regulating mitochondrial architecture and functioning. A deficiency of CL biosynthesis and remodeling perturbs mitochondrial functioning and ultrastructure. [...] Read more.

Cardiolipin (CL) is a unique, tetra-acylated diphosphatidylglycerol lipid that mainly localizes in the inner mitochondria membrane (IMM) in mammalian cells and plays a central role in regulating mitochondrial architecture and functioning. A deficiency of CL biosynthesis and remodeling perturbs mitochondrial functioning and ultrastructure. Clinical and experimental studies on human patients and animal models have also provided compelling evidence that an abnormal CL content, acyl chain composition, localization, and level of oxidation may be directly linked to multiple diseases, including cardiomyopathy, neuronal dysfunction, immune cell defects, and metabolic disorders. The central role of CL in regulating the pathogenesis and progression of these diseases has attracted increasing attention in recent years. In this review, we focus on the advances in our understanding of the physiological roles of CL biosynthesis and remodeling from human patients and mouse models, and we provide an overview of the potential mechanism by which CL regulates the mitochondrial architecture and functioning. Full article

(This article belongs to the Special Issue Cellular and Developmental Biology of Lipid Metabolism)

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14 pages, 326 KiB

Open AccessReview

Multidisciplinary Progress in Obesity Research

by Xiaoqing Lu, Yuxin Jin, Dexin Li, Jingxin Zhang, Jingyan Han and Yin Li

Genes 2022, 13(10), 1772; https://doi.org/10.3390/genes13101772 - 30 Sep 2022

Cited by 8 | Viewed by 2237

Abstract

Obesity is a chronic disease that endangers human health. In recent years, the phenomenon of obesity has become more and more common, and it has become a global epidemic. Obesity is closely associated with many adverse metabolic changes and diseases, such as insulin [...] Read more.

Obesity is a chronic disease that endangers human health. In recent years, the phenomenon of obesity has become more and more common, and it has become a global epidemic. Obesity is closely associated with many adverse metabolic changes and diseases, such as insulin resistance, type 2 diabetes mellitus, coronary heart disease, nervous system diseases and some malignant tumors, which have caused a huge burden on the country’s medical finance. In most countries of the world, the incidence of cancer caused by obesity is increasing year on year. Diabetes associated with obesity can lead to secondary neuropathy. How to treat obesity and its secondary diseases has become an urgent problem for patients, doctors and society. This article will summarize the multidisciplinary research on obesity and its complications. Full article

(This article belongs to the Special Issue Cellular and Developmental Biology of Lipid Metabolism)

28 pages, 2163 KiB

Open AccessReview

Barth Syndrome Cardiomyopathy: An Update

by Jing Pang, Yutong Bao, Kalia Mitchell-Silbaugh, Jennifer Veevers and Xi Fang

Genes 2022, 13(4), 656; https://doi.org/10.3390/genes13040656 - 08 Apr 2022

Cited by 13 | Viewed by 3021

Abstract

Barth syndrome (BTHS) is an X-linked mitochondrial lipid disorder caused by mutations in the TAFAZZIN (TAZ) gene, which encodes a mitochondrial acyltransferase/transacylase required for cardiolipin (CL) biosynthesis. Cardiomyopathy is a major clinical feature of BTHS. During the past four decades, we [...] Read more.

Barth syndrome (BTHS) is an X-linked mitochondrial lipid disorder caused by mutations in the TAFAZZIN (TAZ) gene, which encodes a mitochondrial acyltransferase/transacylase required for cardiolipin (CL) biosynthesis. Cardiomyopathy is a major clinical feature of BTHS. During the past four decades, we have witnessed many landmark discoveries that have led to a greater understanding of clinical features of BTHS cardiomyopathy and their molecular basis, as well as the therapeutic targets for this disease. Recently published Taz knockout mouse models provide useful experimental models for studying BTHS cardiomyopathy and testing potential therapeutic approaches. This review aims to summarize key findings of the clinical features, molecular mechanisms, and potential therapeutic approaches for BTHS cardiomyopathy, with particular emphasis on the most recent studies. Full article

(This article belongs to the Special Issue Cellular and Developmental Biology of Lipid Metabolism)

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