Early disruption of nerve mitochondrial and myelin lipid homeostasis in obesity-induced diabetes

Palavicini, Juan Pablo; Chen, Juan; Wang, Chunyan; Wang, Jianbo; Qin, Chao; Baeuerle, Eric; Wang, Xinming; Woo, Jung A.; Kang, David E.; Musi, Nicolas; Dupree, Jeffrey L.; Han, Xianlin

doi:10.1172/jci.insight.137286

Cited by 30 publications

(18 citation statements)

References 87 publications

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“…The total absolute levels of the four sphingolipid classes analyzed in the cerebrum, brain stem, spinal cord, and sciatic nerve are summarized in Figure 5 , whereas the profiles of the individual molecular species of each of the lipid classes are summarized in Figure S1 . In summary, the following points could be drawn from the study: (1) the total content of these sphingolipids increased from the cerebrum to the brain stem, sciatic nerve, and spinal cord, which largely reflects the differences in the myelin content; (2) the sulfatide content was roughly a third of the cerebroside content in all of the tissues, as has been previously reported [ 12 , 21 ]; and (3) the ratios of cerebroside and SM provide some rough information about the abundance of the myelin sheath relative to the neural cell body membrane, since the former is largely present in the myelin, whereas the latter is largely present in the cellular plasma membrane.…”

Section: Resultssupporting

confidence: 74%

“…Total RNA was isolated after homogenizing nerve tissues in Invitrogen™ TRIzol™ reagent (Thermo Scientific) using a Direct-zol™ RNA MiniPrep kit for RNA isolation (Zymo Research, Catalog #R2050) as previously described [ 12 ]. RNA concentrations were quantified using a NanoDrop 8000 spectrophotometer (Thermo Scientific).…”

Section: Methodsmentioning

confidence: 99%

“…Lipidomics is a rapidly expanding research frontier that studies cellular lipidomes on a large scale [ 9 , 10 , 11 ]. Sphingolipids are essential for brain development and homeostasis, and changes in their molecular species profiles are indicative of an aberrant metabolism and informative about the underlying molecular mechanisms driving such abnormalities [ 12 , 13 ]. For example, the myelin sphingolipid content and/or composition is critical for myelination, myelin maintenance, and myelin function [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

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A Lipidomics Atlas of Selected Sphingolipids in Multiple Mouse Nervous System Regions

Wang

Palavicini

Han

2021

IJMS

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Many lipids, including sphingolipids, are essential components of the nervous system. Sphingolipids play critical roles in maintaining the membrane structure and integrity and in cell signaling. We used a multi-dimensional mass spectrometry-based shotgun lipidomics platform to selectively analyze the lipid species profiles of ceramide, sphingomyelin, cerebroside, and sulfatide; these four classes of sphingolipids are found in the central nervous system (CNS) (the cerebrum, brain stem, and spinal cord) and peripheral nervous system (PNS) (the sciatic nerve) tissues of young adult wild-type mice. Our results revealed that the lipid species profiles of the four sphingolipid classes in the different nervous tissues were highly distinct. In addition, the mRNA expression of sphingolipid metabolism genes—including the ceramidase synthases that specifically acylate the N-acyl chain of ceramide species and sphingomyelinases that cleave sphingomyelins generating ceramides—were analyzed in the mouse cerebrum and spinal cord tissue in order to better understand the sphingolipid profile differences observed between these nervous tissues. We found that the distinct profiles of the determined sphingolipids were consistent with the high selectivity of ceramide synthases and provided a potential mechanism to explain region-specific CNS ceramide and sphingomyelin levels. In conclusion, we portray for the first time a lipidomics atlas of select sphingolipids in multiple nervous system regions and believe that this type of knowledge could be very useful for better understanding the role of this lipid category in the nervous system.

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Section: Resultssupporting

confidence: 74%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Lipidomics Atlas of Selected Sphingolipids in Multiple Mouse Nervous System Regions

Wang

Palavicini

Han

2021

IJMS

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“…Our study did not reveal associations between CAN and any other lipid markers than few phosphatidylcholines. Results from animal models indicate that diabetic neuropathy is associated with disturbances in the lipid metabolism (including triacylglycerols) in nervous tissues ( 38 , 39 ). To our knowledge these findings have not been addressed in people with diabetes.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Autonomic Neuropathy in Type 1 Diabetes Is Associated With Disturbances in TCA, Lipid, and Glucose Metabolism

et al. 2022

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IntroductionDiabetic cardiovascular autonomic neuropathy (CAN) is associated with increased mortality and morbidity. To explore metabolic mechanisms associated with CAN we investigated associations between serum metabolites and CAN in persons with type 1 diabetes (T1D).Materials and MethodsCardiovascular reflex tests (CARTs) (heart rate response to: deep breathing; lying-to-standing test; and the Valsalva maneuver) were used to diagnose CAN in 302 persons with T1D. More than one pathological CARTs defined the CAN diagnosis. Serum metabolomics and lipidomic profiles were analyzed with two complementary non-targeted mass-spectrometry methods. Cross-sectional associations between metabolites and CAN were assessed by linear regression models adjusted for relevant confounders.ResultsParticipants were median (IQR) aged 55(49, 63) years, 48% males with diabetes duration 39(32, 47) years, HbA1c 63(55,69) mmol/mol and 34% had CAN. A total of 75 metabolites and 106 lipids were analyzed. In crude models, the CAN diagnosis was associated with higher levels of hydroxy fatty acids (2,4- and 3,4-dihydroxybutanoic acids, 4−deoxytetronic acid), creatinine, sugar derivates (ribitol, ribonic acid, myo-inositol), citric acid, glycerol, phenols, phosphatidylcholines and lower levels of free fatty acids and the amino acid methionine (p<0.05). Upon adjustment, positive associations with the CAN diagnoses were retained for hydroxy fatty acids, tricarboxylic acid (TCA) cycle-based sugar derivates, citric acid, and phenols (P<0.05).ConclusionMetabolic pathways, including the TCA cycle, hydroxy fatty acids, phosphatidylcholines and sugar derivatives are associated with the CAN diagnosis in T1D. These pathway may be part of the pathogeneses leading to CAN and may be modifiable risk factors for the complication.

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“…Adipose tissue or skeletal muscle samples (10–20mg) were homogenized in ice-cold diluted (10%) phosphate-buffered saline, and lipids were extracted by a modified Bligh and Dyer procedure in the presence of internal standards added based on total protein content, as previously described ( Han and Gross, 2005 ; Wang et al, 2017 ; Palavicini et al, 2020 ). A triple-quadrupole mass spectrometer (Thermo Scientific TSQ Altis, CA, United States) and a Quadrupole-Orbitrap ™ mass spectrometer (Thermo Q Exactive ™ ) equipped with a Nanomate device (Advion Biosciences Ltd., NY, United States) and Xcalibur system software were used as previously described ( Wang et al, 2017 ).…”

Section: Methodsmentioning

confidence: 99%

The Insulin-Sensitizer Pioglitazone Remodels Adipose Tissue Phospholipids in Humans

et al. 2021

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The insulin-sensitizer pioglitazone exerts its cardiometabolic benefits in type 2 diabetes (T2D) through a redistribution of body fat, from ectopic and visceral areas to subcutaneous adipose depots. Whereas excessive weight gain and lipid storage in obesity promotes insulin resistance and chronic inflammation, the expansion of subcutaneous adipose by pioglitazone is associated with a reversal of these immunometabolic deficits. The precise events driving this beneficial remodeling of adipose tissue with pioglitazone remain unclear, and whether insulin-sensitizers alter the lipidomic composition of human adipose has not previously been investigated. Using shotgun lipidomics, we explored the molecular lipid responses in subcutaneous adipose tissue following 6months of pioglitazone treatment (45mg/day) in obese humans with T2D. Despite an expected increase in body weight following pioglitazone treatment, no robust effects were observed on the composition of storage lipids (i.e., triglycerides) or the content of lipotoxic lipid species (e.g., ceramides and diacylglycerides) in adipose tissue. Instead, pioglitazone caused a selective remodeling of the glycerophospholipid pool, characterized by a decrease in lipids enriched for arachidonic acid, such as plasmanylethanolamines and phosphatidylinositols. This contributed to a greater overall saturation and shortened chain length of fatty acyl groups within cell membrane lipids, changes that are consistent with the purported induction of adipogenesis by pioglitazone. The mechanism through which pioglitazone lowered adipose tissue arachidonic acid, a major modulator of inflammatory pathways, did not involve alterations in phospholipase gene expression but was associated with a reduction in its precursor linoleic acid, an effect that was also observed in skeletal muscle samples from the same subjects. These findings offer important insights into the biological mechanisms through which pioglitazone protects the immunometabolic health of adipocytes in the face of increased lipid storage.

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Early disruption of nerve mitochondrial and myelin lipid homeostasis in obesity-induced diabetes

Cited by 30 publications

References 87 publications

A Lipidomics Atlas of Selected Sphingolipids in Multiple Mouse Nervous System Regions

A Lipidomics Atlas of Selected Sphingolipids in Multiple Mouse Nervous System Regions

Cardiovascular Autonomic Neuropathy in Type 1 Diabetes Is Associated With Disturbances in TCA, Lipid, and Glucose Metabolism

The Insulin-Sensitizer Pioglitazone Remodels Adipose Tissue Phospholipids in Humans

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