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Article ; Online: Thermogenic Phenotyping in Mice.

Hu, Donghua / Lodhi, Irfan J

Methods in molecular biology (Clifton, N.J.)

2023 Volume 2662, Page(s) 117–124

Abstract: Thermogenesis mediated by brown adipose tissue (BAT) and brown-like fat plays an important role in regulating metabolic homeostasis in mammals. Accurate measurement of metabolic responses to brown fat activation, including heat generation and increased ... ...

Abstract	Thermogenesis mediated by brown adipose tissue (BAT) and brown-like fat plays an important role in regulating metabolic homeostasis in mammals. Accurate measurement of metabolic responses to brown fat activation, including heat generation and increased energy expenditure is essential for characterizing thermogenic phenotypes in preclinical studies. Here, we describe two methods for assessing thermogenic phenotypes in mice under non-basal states. First, we describe a protocol for measuring body temperature in cold-treated mice using implantable temperature transponders, which allow for continuous monitoring of body temperature. Second, we describe a method for using indirect calorimetry to measure β3-adrenergic agonist-stimulated changes in oxygen consumption, a proxy for thermogenic fat activation.
MeSH term(s)	Animals ; Mice ; Thermogenesis/physiology ; Temperature ; Adipose Tissue, Brown/metabolism ; Cold Temperature ; Body Temperature ; Energy Metabolism/physiology ; Mice, Knockout ; Mice, Inbred C57BL ; Mammals
Language	English
Publishing date	2023-04-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-3167-6_10
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Article ; Online: Peroxisomal regulation of energy homeostasis: Effect on obesity and related metabolic disorders.

Kleiboeker, Brian / Lodhi, Irfan J

Molecular metabolism

2022 Volume 65, Page(s) 101577

Abstract: Background: Peroxisomes are single membrane-bound organelles named for their role in hydrogen peroxide production and catabolism. However, their cellular functions extend well beyond reactive oxygen species (ROS) metabolism and include fatty acid ... ...

Abstract	Background: Peroxisomes are single membrane-bound organelles named for their role in hydrogen peroxide production and catabolism. However, their cellular functions extend well beyond reactive oxygen species (ROS) metabolism and include fatty acid oxidation of unique substrates that cannot be catabolized in mitochondria, and synthesis of ether lipids and bile acids. Metabolic functions of peroxisomes involve crosstalk with other organelles, including mitochondria, endoplasmic reticulum, lipid droplets and lysosomes. Emerging studies suggest that peroxisomes are important regulators of energy homeostasis and that disruption of peroxisomal functions influences the risk for obesity and the associated metabolic disorders, including type 2 diabetes and hepatic steatosis. Scope of review: Here, we focus on the role of peroxisomes in ether lipid synthesis, β-oxidation and ROS metabolism, given that these functions have been most widely studied and have physiologically relevant implications in systemic metabolism and obesity. Efforts are made to mechanistically link these cellular and systemic processes. Major conclusions: Circulating plasmalogens, a form of ether lipids, have been identified as inversely correlated biomarkers of obesity. Ether lipids influence metabolic homeostasis through multiple mechanisms, including regulation of mitochondrial morphology and respiration affecting brown fat-mediated thermogenesis, and through regulation of adipose tissue development. Peroxisomal β-oxidation also affects metabolic homeostasis through generation of signaling molecules, such as acetyl-CoA and ROS that inhibit hydrolysis of stored lipids, contributing to development of hepatic steatosis. Oxidative stress resulting from increased peroxisomal β-oxidation-generated ROS in the context of obesity mediates β-cell lipotoxicity. A better understanding of the roles peroxisomes play in regulating and responding to obesity and its complications will provide new opportunities for their treatment.
MeSH term(s)	Acetyl Coenzyme A ; Bile Acids and Salts ; Diabetes Mellitus, Type 2 ; Ethers ; Fatty Acids/metabolism ; Homeostasis ; Humans ; Hydrogen Peroxide ; Obesity ; Plasmalogens ; Reactive Oxygen Species/metabolism
Chemical Substances	Bile Acids and Salts ; Ethers ; Fatty Acids ; Plasmalogens ; Reactive Oxygen Species ; Acetyl Coenzyme A (72-89-9) ; Hydrogen Peroxide (BBX060AN9V)
Language	English
Publishing date	2022-08-19
Publishing country	Germany
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2708735-9
ISSN	2212-8778 ; 2212-8778
ISSN (online)	2212-8778
ISSN	2212-8778
DOI	10.1016/j.molmet.2022.101577
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Article ; Online: Isolation and Mass Spectrometry-Based Profiling of Major Lipids in Brown Adipose Tissue.

Lu, Dongliang / Fujiwara, Hideji / Lodhi, Irfan J / Hsu, Fong-Fu

Methods in molecular biology (Clifton, N.J.)

2023 Volume 2662, Page(s) 219–239

Abstract: Brown adipose tissue (BAT) is an important regulator of metabolic homeostasis through its role in adaptive thermogenesis and control of whole-body glucose metabolism. Lipids play multiple roles in BAT functions, including serving as a fuel source for ... ...

Abstract	Brown adipose tissue (BAT) is an important regulator of metabolic homeostasis through its role in adaptive thermogenesis and control of whole-body glucose metabolism. Lipids play multiple roles in BAT functions, including serving as a fuel source for thermogenesis, mediating inter-organelle cross talk, and acting as BAT-derived signaling molecules that influence systemic energy metabolism. Profiling of various lipids in BAT under distinct metabolic states could provide new insights into their roles in the biology of the thermogenic fat. In this chapter, we describe a step-by-step workflow starting from sample preparations to mass spectrometry-based analysis of fatty acids and phospholipids in BAT.
MeSH term(s)	Adipose Tissue, Brown/metabolism ; Energy Metabolism ; Thermogenesis ; Homeostasis ; Fatty Acids/metabolism
Chemical Substances	Fatty Acids
Language	English
Publishing date	2023-03-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-3167-6_20
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Article ; Online: Peroxisomes as cellular adaptors to metabolic and environmental stress.

He, Anyuan / Dean, John M / Lodhi, Irfan J

Trends in cell biology

2021 Volume 31, Issue 8, Page(s) 656–670

Abstract: Peroxisomes are involved in multiple metabolic processes, including fatty acid oxidation, ether lipid synthesis, and reactive oxygen species (ROS) metabolism. Recent studies suggest that peroxisomes are critical mediators of cellular responses to various ...

Abstract	Peroxisomes are involved in multiple metabolic processes, including fatty acid oxidation, ether lipid synthesis, and reactive oxygen species (ROS) metabolism. Recent studies suggest that peroxisomes are critical mediators of cellular responses to various forms of stress, including oxidative stress, hypoxia, starvation, cold exposure, and noise. As dynamic organelles, peroxisomes can modulate their proliferation, morphology, and movement within cells, and engage in crosstalk with other organelles in response to external cues. Although peroxisome-derived hydrogen peroxide has a key role in cellular signaling related to stress, emerging studies suggest that other products of peroxisomal metabolism, such as acetyl-CoA and ether lipids, are also important for metabolic adaptation to stress. Here, we review molecular mechanisms through which peroxisomes regulate metabolic and environmental stress.
MeSH term(s)	Lipid Metabolism ; Oxidation-Reduction ; Oxidative Stress ; Peroxisomes/metabolism ; Reactive Oxygen Species/metabolism
Chemical Substances	Reactive Oxygen Species
Language	English
Publishing date	2021-03-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	30122-x
ISSN	1879-3088 ; 0962-8924
ISSN (online)	1879-3088
ISSN	0962-8924
DOI	10.1016/j.tcb.2021.02.005
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Article ; Online: Structural and functional roles of ether lipids.

Dean, John M / Lodhi, Irfan J

Protein & cell

2017 Volume 9, Issue 2, Page(s) 196–206

Abstract: Ether lipids, such as plasmalogens, are peroxisome-derived glycerophospholipids in which the hydrocarbon chain at the sn-1 position of the glycerol backbone is attached by an ether bond, as opposed to an ester bond in the more common diacyl phospholipids. ...

Abstract	Ether lipids, such as plasmalogens, are peroxisome-derived glycerophospholipids in which the hydrocarbon chain at the sn-1 position of the glycerol backbone is attached by an ether bond, as opposed to an ester bond in the more common diacyl phospholipids. This seemingly simple biochemical change has profound structural and functional implications. Notably, the tendency of ether lipids to form non-lamellar inverted hexagonal structures in model membranes suggests that they have a role in facilitating membrane fusion processes. Ether lipids are also important for the organization and stability of lipid raft microdomains, cholesterol-rich membrane regions involved in cellular signaling. In addition to their structural roles, a subset of ether lipids are thought to function as endogenous antioxidants, and emerging studies suggest that they are involved in cell differentiation and signaling pathways. Here, we review the biology of ether lipids and their potential significance in human disorders, including neurological diseases, cancer, and metabolic disorders.
MeSH term(s)	Animals ; Disease ; Ether/chemistry ; Humans ; Lipid Metabolism ; Lipids/chemistry
Chemical Substances	Lipids ; Ether (0F5N573A2Y)
Language	English
Publishing date	2017-05-18
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2543451-2
ISSN	1674-8018 ; 1674-8018
ISSN (online)	1674-8018
ISSN	1674-8018
DOI	10.1007/s13238-017-0423-5
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Article ; Online: Peroxisomal Dysfunction in Age-Related Diseases.

Cipolla, Cynthia M / Lodhi, Irfan J

Trends in endocrinology and metabolism: TEM

2017 Volume 28, Issue 4, Page(s) 297–308

Abstract: Peroxisomes carry out many key functions related to lipid and reactive oxygen species (ROS) metabolism. The fundamental importance of peroxisomes for health in humans is underscored by the existence of devastating genetic disorders caused by impaired ... ...

Abstract	Peroxisomes carry out many key functions related to lipid and reactive oxygen species (ROS) metabolism. The fundamental importance of peroxisomes for health in humans is underscored by the existence of devastating genetic disorders caused by impaired peroxisomal function or lack of peroxisomes. Emerging studies suggest that peroxisomal function may also be altered with aging and contribute to the pathogenesis of a variety of diseases, including diabetes and its related complications, neurodegenerative disorders, and cancer. With increasing evidence connecting peroxisomal dysfunction to the pathogenesis of these acquired diseases, the possibility of targeting peroxisomal function in disease prevention or treatment becomes intriguing. Here, we review recent developments in understanding the pathophysiological implications of peroxisomal dysfunctions outside the context of inherited peroxisomal disorders.
MeSH term(s)	Aging/physiology ; Animals ; Humans ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology ; Neurodegenerative Diseases/physiopathology ; Oxidative Stress/physiology ; Peroxisomes/metabolism ; Reactive Oxygen Species/metabolism
Chemical Substances	Reactive Oxygen Species
Language	English
Publishing date	2017-01-04
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	1042384-9
ISSN	1879-3061 ; 1043-2760
ISSN (online)	1879-3061
ISSN	1043-2760
DOI	10.1016/j.tem.2016.12.003
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Zs.A 2999: Show issues

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Article ; Online: Adipose tissue peroxisomal lipid synthesis orchestrates obesity and insulin resistance through LXR-dependent lipogenesis.

Kleiboeker, Brian / He, Anyuan / Tan, Min / Lu, Dongliang / Hu, Donghua / Liu, Xuejing / Goodarzi, Parniyan / Hsu, Fong-Fu / Razani, Babak / Semenkovich, Clay F / Lodhi, Irfan J

Molecular metabolism

2024 Volume 82, Page(s) 101913

Abstract: Objective: Adipose tissue mass is maintained by a balance between lipolysis and lipid storage. The contribution of adipose tissue lipogenesis to fat mass, especially in the setting of high-fat feeding, is considered minor. Here we investigated the ... ...

Abstract	Objective: Adipose tissue mass is maintained by a balance between lipolysis and lipid storage. The contribution of adipose tissue lipogenesis to fat mass, especially in the setting of high-fat feeding, is considered minor. Here we investigated the effect of adipose-specific inactivation of the peroxisomal lipid synthetic protein PexRAP on fatty acid synthase (FASN)-mediated lipogenesis and its impact on adiposity and metabolic homeostasis. Methods: To explore the role of PexRAP in adipose tissue, we metabolically phenotyped mice with adipose-specific knockout of PexRAP. Bulk RNA sequencing was used to determine transcriptomic responses to PexRAP deletion and Results: Adipose-specific PexRAP deletion promoted diet-induced obesity and insulin resistance through activation of de novo lipogenesis. Mechanistically, PexRAP inactivation inhibited the flux of carbons to ethanolamine plasmalogens. This increased the nuclear PC/PE ratio and promoted cholesterol mislocalization, resulting in activation of liver X receptor (LXR), a nuclear receptor known to be activated by increased intracellular cholesterol. LXR activation led to increased expression of the phospholipid remodeling enzyme LPCAT3 and induced FASN-mediated lipogenesis, which promoted diet-induced obesity and insulin resistance. Conclusions: These studies reveal an unexpected role for peroxisome-derived lipids in regulating LXR-dependent lipogenesis and suggest that activation of lipogenesis, combined with dietary lipid overload, exacerbates obesity and metabolic dysregulation.
MeSH term(s)	Animals ; Mice ; 1-Acylglycerophosphocholine O-Acyltransferase/metabolism ; Adipose Tissue/metabolism ; Cholesterol/metabolism ; Dietary Fats/metabolism ; Insulin Resistance ; Lipogenesis/genetics ; Liver X Receptors/metabolism ; Mice, Knockout ; Obesity/metabolism
Chemical Substances	1-Acylglycerophosphocholine O-Acyltransferase (EC 2.3.1.23) ; Cholesterol (97C5T2UQ7J) ; Dietary Fats ; Liver X Receptors ; LPCAT3 protein, mouse (EC 2.3.1.23) ; Nr1h3 protein, mouse
Language	English
Publishing date	2024-03-07
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2708735-9
ISSN	2212-8778 ; 2212-8778
ISSN (online)	2212-8778
ISSN	2212-8778
DOI	10.1016/j.molmet.2024.101913
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Article ; Online: Lipid Regulators of Thermogenic Fat Activation.

Park, Hongsuk / He, Anyuan / Lodhi, Irfan J

Trends in endocrinology and metabolism: TEM

2019 Volume 30, Issue 10, Page(s) 710–723

Abstract: The global prevalence of obesity continues to increase, suggesting a need for alternative treatment approaches. Targeting brown fat function to promote energy expenditure represents one such approach. Brown adipocytes and the related beige adipocytes ... ...

Abstract	The global prevalence of obesity continues to increase, suggesting a need for alternative treatment approaches. Targeting brown fat function to promote energy expenditure represents one such approach. Brown adipocytes and the related beige adipocytes oxidize fatty acids and glucose to generate heat and are activated by cold exposure or consumption of high-calorie diets. Alternative, more practical means to activate thermogenic fat are needed. Here, we review emerging data suggesting new roles for lipids in activating thermogenesis that extend beyond their serving as a fuel source for heat generation. Lipids have also been implicated in mediating interorgan communication, crosstalk between organelles, and cellular signaling regulating thermogenesis. Understanding how lipids regulate thermogenesis could identify innovative therapeutic interventions for obesity.
MeSH term(s)	Adipose Tissue, Beige/metabolism ; Animals ; Humans ; Mitochondria/metabolism ; Obesity/metabolism ; Plasmalogens/metabolism ; Thermogenesis/physiology
Chemical Substances	Plasmalogens
Language	English
Publishing date	2019-08-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1042384-9
ISSN	1879-3061 ; 1043-2760
ISSN (online)	1879-3061
ISSN	1043-2760
DOI	10.1016/j.tem.2019.07.020
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Article ; Online: Hepatic peroxisomal β-oxidation suppresses lipophagy via RPTOR acetylation and MTOR activation.

He, Anyuan / Dean, John M / Lu, Dongliang / Chen, Yali / Lodhi, Irfan J

Autophagy

2020 Volume 16, Issue 9, Page(s) 1727–1728

Abstract: Hepatic lipid homeostasis is controlled by a coordinated regulation of various metabolic pathways involved in de novo synthesis, uptake, storage, and catabolism of lipids. Disruption of this balance could lead to hepatic steatosis. Peroxisomes play an ... ...

Abstract	Hepatic lipid homeostasis is controlled by a coordinated regulation of various metabolic pathways involved in de novo synthesis, uptake, storage, and catabolism of lipids. Disruption of this balance could lead to hepatic steatosis. Peroxisomes play an essential role in lipid metabolism, yet their importance is often overlooked. In a recent study, we demonstrated a role for hepatic peroxisomal β-oxidation in autophagic degradation of lipid droplets. ACOX1 (acyl-Coenzyme A oxidase 1, palmitoyl), the rate-limiting enzyme of peroxisomal β-oxidation, increases with fasting or high-fat diet (HFD). Liver-specific
MeSH term(s)	Acetyl Coenzyme A/metabolism ; Acetylation ; Animals ; Autophagy ; Humans ; Lipid Droplets/metabolism ; Liver/metabolism ; Mice, Knockout ; Models, Biological ; Oxidation-Reduction ; Peroxisomes/metabolism ; Regulatory-Associated Protein of mTOR/metabolism ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Regulatory-Associated Protein of mTOR ; Acetyl Coenzyme A (72-89-9) ; TOR Serine-Threonine Kinases (EC 2.7.1.1)
Language	English
Publishing date	2020-07-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2020.1797288
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Article ; Online: Peroxisomes: a nexus for lipid metabolism and cellular signaling.

Lodhi, Irfan J / Semenkovich, Clay F

Cell metabolism

2014 Volume 19, Issue 3, Page(s) 380–392

Abstract: Peroxisomes are often dismissed as the cellular hoi polloi, relegated to cleaning up reactive oxygen chemical debris discarded by other organelles. However, their functions extend far beyond hydrogen peroxide metabolism. Peroxisomes are intimately ... ...

Abstract	Peroxisomes are often dismissed as the cellular hoi polloi, relegated to cleaning up reactive oxygen chemical debris discarded by other organelles. However, their functions extend far beyond hydrogen peroxide metabolism. Peroxisomes are intimately associated with lipid droplets and mitochondria, and their ability to carry out fatty acid oxidation and lipid synthesis, especially the production of ether lipids, may be critical for generating cellular signals required for normal physiology. Here, we review the biology of peroxisomes and their potential relevance to human disorders including cancer, obesity-related diabetes, and degenerative neurologic disease.
MeSH term(s)	Adipocytes/metabolism ; Fatty Acids/chemistry ; Fatty Acids/metabolism ; Humans ; Lipid Metabolism/physiology ; Mitochondria/metabolism ; PPAR gamma/metabolism ; Peroxisomal Disorders/metabolism ; Peroxisomal Disorders/pathology ; Peroxisomes/metabolism ; Phospholipid Ethers/metabolism ; Signal Transduction
Chemical Substances	Fatty Acids ; PPAR gamma ; Phospholipid Ethers
Language	English
Publishing date	2014-02-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2014.01.002
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