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Biology of Sex Differences Sep 2023Sex differences have been observed in the development of obesity-related complications in patients, as well as in animal models. Accumulating evidence suggests that...
BACKGROUND
Sex differences have been observed in the development of obesity-related complications in patients, as well as in animal models. Accumulating evidence suggests that sex-dependent regulation of lipid metabolism contributes to sex-specific physiopathology. Lipid accumulation in the renal tissue has been shown to play a major role in the pathogenesis of obesity-induced kidney injury. Unlike in males, the physiopathology of the disease has been poorly described in females, particularly regarding the lipid metabolism adaptation.
METHODS
Here, we compared the lipid profile changes in the kidneys of female and male mice fed a high-fat diet (HFD) or low-fat diet (LFD) by lipidomics and correlated them with pathophysiological changes.
RESULTS
We showed that HFD-fed female mice were protected from insulin resistance and hepatic steatosis compared to males, despite similar body weight gains. Females were particularly protected from renal dysfunction, oxidative stress, and tubular lipid accumulation. Both HFD-fed male and female mice presented dyslipidemia, but lipidomic analysis highlighted differential renal lipid profiles. While both sexes presented similar neutral lipid accumulation with obesity, only males showed increased levels of ceramides and phospholipids. Remarkably, protection against renal lipotoxicity in females was associated with enhanced renal adiponectin and AMP-activated protein kinase (AMPK) signaling. Circulating adiponectin and its renal receptor levels were significantly lower in obese males, but were maintained in females. This observation correlated with the maintained basal AMPK activity in obese female mice compared to males.
CONCLUSIONS
Collectively, our findings suggest that female mice are protected from obesity-induced renal dysfunction and lipotoxicity associated with enhanced adiponectin and AMPK signaling compared to males.
Topics: Animals; Female; Male; Mice; Adiponectin; AMP-Activated Protein Kinases; Kidney; Kidney Diseases; Lipidomics; Lipids; Obesity; Sex Characteristics
PubMed: 37770988
DOI: 10.1186/s13293-023-00543-6 -
Genes Oct 2023Perivascular adipose tissue (PVAT) regulates vascular function by secreting vasoactive substances. In mice, Notch signaling is activated in the PVAT during diet-induced...
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 () strain to activate a ligand-independent Notch1 intracellular domain transgene () to drive constitutive Notch signaling in the adipose tissues (). 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 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 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.
Topics: Mice; Animals; Proteomics; Adipose Tissue; Signal Transduction; Obesity; Adiponectin; Mitochondria
PubMed: 37895313
DOI: 10.3390/genes14101964 -
The Journal of Clinical Investigation Jan 2024Choline deficiency causes disorders including hepatic abnormalities and is associated with an increased risk of multiple types of cancer. Here, by choline-free...
Choline deficiency causes disorders including hepatic abnormalities and is associated with an increased risk of multiple types of cancer. Here, by choline-free diet-associated RNA-Seq analyses, we found that the tumor suppressor p53 drives the Kennedy pathway via PCYT1B to control the growth of lipid droplets (LDs) and their fueling role in tumorigenesis. Mechanistically, through upregulation of PCYT1B, p53 channeled depleted choline stores to phosphatidylcholine (PC) biosynthesis during choline starvation, thus preventing LD coalescence. Cells lacking p53 failed to complete this response to choline depletion, leading to hepatic steatosis and tumorigenesis, and these effects could be reversed by enforcement of PCYT1B expression or restoration of PC abundance. Furthermore, loss of p53 or defects in the Kennedy pathway increased surface localization of hormone-sensitive lipase on LDs to release specific fatty acids that fueled tumor cells in vivo and in vitro. Thus, p53 loss leads to dysregulation of choline metabolism and LD growth and couples perturbed LD homeostasis to tumorigenesis.
Topics: Humans; Lipid Droplets; Phosphatidylcholines; Tumor Suppressor Protein p53; Carcinogenesis; Cell Transformation, Neoplastic; Choline; Lipid Metabolism; Choline-Phosphate Cytidylyltransferase
PubMed: 38194288
DOI: 10.1172/JCI171788 -
FASEB Journal : Official Publication of... Jul 2023The phospholipase A and acyltransferase (PLAAT) family is composed of three isoforms in mice (PLAAT1, 3, and 5), all of which function as phospholipid-metabolizing...
The phospholipase A and acyltransferase (PLAAT) family is composed of three isoforms in mice (PLAAT1, 3, and 5), all of which function as phospholipid-metabolizing enzymes exhibiting phospholipase A /A and acyltransferase activities. Plaat3-deficient (Plaat3 ) mice were previously reported to show lean phenotype and remarkable hepatic fat accumulation under high-fat diet (HFD) feeding, while Plaat1 mice have not been analyzed. In the present study, we generated Plaat1 mice and investigated the effects of PLAAT1 deficiency on HFD-induced obesity, hepatic lipid accumulation, and insulin resistance. After HFD treatment, PLAAT1 deficiency caused a lower body weight gain compared to wild-type mice. Plaat1 mice also showed reduced liver weight with negligible hepatic lipid accumulation. In accordance with these findings, PLAAT1 deficiency improved HFD-induced hepatic dysfunction and lipid metabolism disorders. Lipidomics analysis in the liver revealed that in Plaat1 mice, the levels of various glycerophospholipids tended to increase, while all classes of lysophospholipids examined tended to decrease, suggesting that PLAAT1 functions as phospholipase A /A in the liver. Interestingly, the HFD treatment of wild-type mice significantly increased the mRNA level of PLAAT1 in the liver. Furthermore, the deficiency did not appear to elevate the risk of insulin resistance in contrast to PLAAT3 deficiency. These results suggested that the suppression of PLAAT1 improves HFD-induced overweight and concomitant hepatic lipid accumulation.
Topics: Animals; Mice; Diet, High-Fat; Insulin Resistance; Lipid Metabolism; Liver; Phospholipids; Phospholipases; Acyltransferases; Mice, Inbred C57BL
PubMed: 37330992
DOI: 10.1096/fj.202201033R -
FASEB Journal : Official Publication of... Jul 2023Docosahexaenoic (DHA) and arachidonic acids (ARA) are omega-3 and omega-6 long-chain polyunsaturated fatty acids (LCPUFAs). These molecules constitute a substantial...
Unsaturated fatty acids uniquely alter aggregation rate of α-synuclein and insulin and change the secondary structure and toxicity of amyloid aggregates formed in their presence.
Docosahexaenoic (DHA) and arachidonic acids (ARA) are omega-3 and omega-6 long-chain polyunsaturated fatty acids (LCPUFAs). These molecules constitute a substantial portion of phospholipids in plasma membranes. Therefore, both DHA and ARA are essential diet components. Once consumed, DHA and ARA can interact with a large variety of biomolecules, including proteins such as insulin and α-synuclein (α-Syn). Under pathological conditions known as injection amyloidosis and Parkinson's disease, these proteins aggregate forming amyloid oligomers and fibrils, toxic species that exert high cell toxicity. In this study, we investigate the role of DHA and ARA in the aggregation properties of α-Syn and insulin. We found that the presence of both DHA and ARA at the equimolar concentrations strongly accelerated aggregation rates of α-Syn and insulin. Furthermore, LCPUFAs substantially altered the secondary structure of protein aggregates, whereas no noticeable changes in the fibril morphology were observed. Nanoscale Infrared analysis of α-Syn and insulin fibrils grown in the presence of both DHA and ARA revealed the presence of LCPUFAs in these aggregates. We also found that such LCPUFAs-rich α-Syn and insulin fibrils exerted significantly greater toxicities compared to the aggregates grown in the LCPUFAs-free environment. These findings show that interactions between amyloid-associated proteins and LCPUFAs can be the underlying molecular cause of neurodegenerative diseases.
Topics: Humans; alpha-Synuclein; Insulin; Fatty Acids, Omega-3; Parkinson Disease; Amyloid; Fatty Acids, Unsaturated; Amyloidogenic Proteins; Arachidonic Acids
PubMed: 37302013
DOI: 10.1096/fj.202300003R -
European Review For Medical and... Jul 2023Berberine is a plant alkaloid known to exert positive metabolic effects. Human studies have confirmed its ability to improve the lipid and glycemic profile. This study... (Randomized Controlled Trial)
Randomized Controlled Trial
Berberine phospholipid exerts a positive effect on the glycemic profile of overweight subjects with impaired fasting blood glucose (IFG): a randomized double-blind placebo-controlled clinical trial.
OBJECTIVE
Berberine is a plant alkaloid known to exert positive metabolic effects. Human studies have confirmed its ability to improve the lipid and glycemic profile. This study aimed to evaluate the potential benefit of oral supplementation of Berberine PhytosomeTM (2 tablets/day, 550 mg/tablet) on the metabolic profile of subjects with impaired fasting blood glucose (IFG).
PATIENTS AND METHODS
A total of 49 overweight subjects, 28 females and 21 males, were randomly assigned to either the supplemented group (n=24) or placebo (n=25). We considered glycemia as the primary endpoint and total cholesterol, high-density lipoprotein (HDL), total cholesterol/HLD, low-density lipoprotein (LDL), LDL/HDL, triglycerides, insulin, glycated hemoglobin, Homeostasis Model Assessment (HOMA), ApoA, ApoB, ApoB/ApoA, androgen suppression treatment (AST), alternative lengthening of telomeres (ALT), gamma-glutamyl transferase (GGT), creatinine, and body composition by dual-energy X-ray absorptiometry (DXA) as secondary endpoints. These parameters have been assessed at baseline, after 30 days, and after 60 days.
RESULTS
After two months of treatment, through the use of linear mixed effect models, a statistically significant difference between supplemented and placebo groups was observed for glycemia [β=-0.2495% C.I. (-0.47; -0.06), p=0.004], total cholesterol [β=-0.25, 95% C.I. (-0.45; -0.04), p=0.05], total cholesterol/HDL [β=-0.25, 95% C.I. (-0.43; -0.06), p=0.04], triglycerides [β=-0.14, 95% C.I. (-0.25; -0.02), p=0.05], insulin [β=-1.78, 95% C.I. (-2.87; -0.66), p=0.009], ApoB/ApoA [β=-0.08, 95% C.I. (-0.13; -03), p=0.004], Visceral adipose tissue (VAT) [β=-91.50, 95% C.I. (-132.60; -48.19), p<0.0001] and fat mass [β=-945.56, 95% C.I. (-1,424.42; -441.57), p=0.004].
CONCLUSIONS
The use of berberine had no adverse events, supporting its use as a natural alternative to pharmacological therapies in the case of IFG.
Topics: Male; Female; Humans; Overweight; Blood Glucose; Berberine; Phospholipids; Triglycerides; Insulin; Lipoproteins, HDL; Cholesterol; Apolipoproteins A; Apolipoproteins B; Fasting; Double-Blind Method
PubMed: 37522683
DOI: 10.26355/eurrev_202307_33142 -
Cardiovascular Diabetology Mar 2024In this study, we evaluated the lipidome alterations caused by type 1 diabetes (T1D) and type 2 diabetes (T2D), by determining lipids significantly associated with...
BACKGROUND
In this study, we evaluated the lipidome alterations caused by type 1 diabetes (T1D) and type 2 diabetes (T2D), by determining lipids significantly associated with diabetes overall and in both sexes, and lipids associated with the glycaemic state.
METHODS
An untargeted lipidomic analysis was performed to measure the lipid profiles of 360 subjects (91 T1D, 91 T2D, 74 with prediabetes and 104 controls (CT)) without cardiovascular and/or chronic kidney disease. Ultra-high performance liquid chromatography-electrospray ionization mass spectrometry (UHPLC-ESI-MS) was conducted in two ion modes (positive and negative). We used multiple linear regression models to (1) assess the association between each lipid feature and each condition, (2) determine sex-specific differences related to diabetes, and (3) identify lipids associated with the glycaemic state by considering the prediabetes stage. The models were adjusted by sex, age, hypertension, dyslipidaemia, body mass index, glucose, smoking, systolic blood pressure, triglycerides, HDL cholesterol, LDL cholesterol, alternate Mediterranean diet score (aMED) and estimated glomerular filtration rate (eGFR); diabetes duration and glycated haemoglobin (HbA1c) were also included in the comparison between T1D and T2D.
RESULTS
A total of 54 unique lipid subspecies from 15 unique lipid classes were annotated. Lysophosphatidylcholines (LPC) and ceramides (Cer) showed opposite effects in subjects with T1D and subjects with T2D, LPCs being mainly up-regulated in T1D and down-regulated in T2D, and Cer being up-regulated in T2D and down-regulated in T1D. Also, Phosphatidylcholines were clearly down-regulated in subjects with T1D. Regarding sex-specific differences, ceramides and phosphatidylcholines exhibited important diabetes-associated differences due to sex. Concerning the glycaemic state, we found a gradual increase of a panel of 1-deoxyceramides from normoglycemia to prediabetes to T2D.
CONCLUSIONS
Our findings revealed an extensive disruption of lipid metabolism in both T1D and T2D. Additionally, we found sex-specific lipidome changes associated with diabetes, and lipids associated with the glycaemic state that can be linked to previously described molecular mechanisms in diabetes.
Topics: Male; Female; Humans; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1; Lipidomics; Prediabetic State; Cholesterol, HDL; Ceramides; Phosphatidylcholines
PubMed: 38553758
DOI: 10.1186/s12933-024-02202-5 -
The Journal of Nutritional Biochemistry Oct 2023Ferroptosis is an iron-dependent form of programmed cell death driven by excessive oxidation of polyunsaturated phospholipids on cellular membranes. Accumulating... (Review)
Review
Ferroptosis is an iron-dependent form of programmed cell death driven by excessive oxidation of polyunsaturated phospholipids on cellular membranes. Accumulating evidence suggests that ferroptosis has been implicated in the pathological process of various diseases, such as cardiovascular diseases, neurological diseases, liver diseases, kidney injury, lung injury, diabetes, and cancer. Targeting ferroptosis is therefore considered to be a reasonable strategy to fight against ferroptosis-associated diseases. Many dietary bioactive agents have been identified to be able to either suppress or promote ferroptosis, indicating that ferroptosis-based intervention by dietary approach may be an effective strategy for preventing and treating diseases associated with ferroptosis dysregulation. In this review, we summarize the present understanding of the functional role of ferroptosis in the pathogenesis of aforementioned diseases with an emphasis on the evidence of managing ferroptosis-related diseases with indirect dietary modulators of ferroptosis and propose issues that need to be addressed to promote practical application of dietary approach targeting ferroptosis.
Topics: Humans; Ferroptosis; Apoptosis; Cardiovascular Diseases; Cell Membrane; Diet; Lipid Peroxidation
PubMed: 37549833
DOI: 10.1016/j.jnutbio.2023.109427 -
Molecular Metabolism Dec 2023Genome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study...
BACKGROUND AND AIMS
Genome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the role of liver-specific CPT1a on hepatic lipid metabolism.
APPROACH AND RESULTS
Male and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (60% kcal fat) for 15 weeks. Mice were necropsied after a 16 h fast, and tissues were collected for lipidomics, matrix-assisted laser desorption ionization mass spectrometry imaging, kinome analysis, RNA-sequencing, and protein expression by immunoblotting. Female LKO mice had increased serum alanine aminotransferase levels which were associated with greater deposition of hepatic lipids, while male mice were not affected by CPT1a deletion relative to male control mice. Mice with CPT1a deletion had reductions in DHA-containing phospholipids at the expense of monounsaturated fatty acids (MUFA)-containing phospholipids in whole liver and at the level of the lipid droplet (LD). Male and female LKO mice increased RNA levels of genes involved in LD lipolysis (Plin2, Cidec, G0S2) and in polyunsaturated fatty acid metabolism (Elovl5, Fads1, Elovl2), while only female LKO mice increased genes involved in inflammation (Ly6d, Mmp12, Cxcl2). Kinase profiling showed decreased protein kinase A activity, which coincided with increased PLIN2, PLIN5, and G0S2 protein levels and decreased triglyceride hydrolysis in LKO mice.
CONCLUSIONS
Liver-specific deletion of CPT1a promotes sexually dimorphic steatotic liver disease (SLD) in mice, and here we have identified new mechanisms by which females are protected from HFD-induced liver injury.
Topics: Female; Male; Animals; Mice; Docosahexaenoic Acids; Phospholipids; Carnitine O-Palmitoyltransferase; Fatty Liver; RNA
PubMed: 37797918
DOI: 10.1016/j.molmet.2023.101815 -
Diabetes Nov 2023Cell membrane phosphatidylcholine (PC) composition is regulated by lysophosphatidylcholine acyltransferase (LPCAT); changes in membrane PC saturation are implicated in...
Cell membrane phosphatidylcholine (PC) composition is regulated by lysophosphatidylcholine acyltransferase (LPCAT); changes in membrane PC saturation are implicated in metabolic disorders. Here, we identified LPCAT3 as the major isoform of LPCAT in adipose tissue and created adipocyte-specific Lpcat3-knockout mice to study adipose tissue lipid metabolism. Transcriptome sequencing and plasma adipokine profiling were used to investigate how LPCAT3 regulates adipose tissue insulin signaling. LPCAT3 deficiency reduced polyunsaturated PCs in adipocyte plasma membranes, increasing insulin sensitivity. LPCAT3 deficiency influenced membrane lipid rafts, which activated insulin receptors and AKT in adipose tissue, and attenuated diet-induced insulin resistance. Conversely, higher LPCAT3 activity in adipose tissue from ob/ob, db/db, and high-fat diet-fed mice reduced insulin signaling. Adding polyunsaturated PCs to mature human or mouse adipocytes in vitro worsened insulin signaling. We suggest that targeting LPCAT3 in adipose tissue to manipulate membrane phospholipid saturation is a new strategy to treat insulin resistance.
Topics: Humans; Animals; Mice; Phosphatidylcholines; Insulin Resistance; Adipose Tissue; Phospholipids; Insulin; Mice, Inbred C57BL; Diet, High-Fat; 1-Acylglycerophosphocholine O-Acyltransferase
PubMed: 37625119
DOI: 10.2337/db23-0317