Role of hypothalamic de novo ceramides synthesis in obesity and associated metabolic disorders

Magnan, Christophe; Stunff, Hervé Le

doi:10.1016/j.molmet.2021.101298

Cited by 14 publications

(11 citation statements)

References 96 publications

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“…We speculate that decreased body weight gain in CerS6 KO mice might be due to reduced food consumption and an increased rate of energy expenditure, which agrees with previous studies. Accrual of hypothalamic ceramides stimulates orexigenic pathways, dysregulates energy balance, and further perturbs glucose homeostasis in mice models [25]. In addition, central administration of a cell-permeable C 6:0 -ceramide analogue to the hypothalamus increases hypothalamic C 16:0 -ceramides, and subsequently increases body weight, which might emphasize the pathological role of C 16:0 -ceramides in obesity [26].…”

Section: Discussionmentioning

confidence: 99%

Ceramide synthase 6 (CerS6) promotes alcohol-induced fatty liver by promoting metabolic dysfunction and upregulating lipid droplet-associated proteins

Jeon

Scorletti

Buyco

et al. 2022

Preprint

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Objective: Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality worldwide. Current strategies to manage ALD largely focus on advanced stage disease, however, metabolic changes such as glucose intolerance are apparent at the earliest stage of alcoholic steatosis and increase the risk of disease progression. Ceramides impair insulin signaling and accumulate in ALD, and metabolic pathways involving ceramide synthase 6 (CerS6) are perturbed in ALD during hepatic steatosis. In this study, we aimed to investigate the role of CerS6 in ALD development. Methods: C57BL/6 WT and CerS6 KO mice of both sexes were fed either a Lieber-DeCarli control (CON) or 15% ethanol (EtOH) diet for 6 weeks. In vivo metabolic tests including glucose and insulin tolerance tests (GTT and ITT) were performed. The mice were euthanized, and liver histology and lipid levels in serum and liver were measured. For in vitro studies, CerS6 was deleted in human hepatocytes and were incubated with EtOH and/or C16:0-ceramides. RNAseq analysis was performed in mice and in liver from patients with different stages of ALD and diseased controls. Results: After six weeks on an EtOH diet, CerS6 KO mice had reduced body weight, food intake, and %fat mass compared to WT mice. Male (but not female) EtOH-fed KO mice showed significantly higher O2 consumption, CO2 production, respiratory exchange ratio, and energy expenditure (P<0.05 for all) during the dark period compared to EtOH-fed WT mice. In response to EtOH, WT mice developed mild hepatic steatosis, while steatosis was alleviated in KO mice as determined by H&E and ORO staining. KO mice showed significantly decreased long-chain ceramide species, especially C16:0 ceramides, in the serum and liver tissues compared to WT mice. CerS6 deletion decreased serum TG and NEFA only in male not female mice. CerS6 deletion improved glucose tolerance and insulin resistance in EtOH-fed mice of both sexes. RNAseq analysis revealed that 74 genes are significantly upregulated and 66 genes are downregulated by CerS6 deletion in EtOH-fed male mice, with key network pathways including TG biosynthetic process, positive regulation of lipid localization, and fat cell differentiation. Similar to RNAseq results, absence of CerS6 significantly decreased mRNA expression of lipid droplet associated proteins in EtOH-fed mice. In vitro, EtOH stimulation significantly increased PLIN2 protein expression in VL-17A cells while CerS6 deletion inhibited EtOH-mediated PLIN2 upregulation. C16:0-ceramide treatment significantly increased PLIN2 protein expression compared to CON. Importantly, progression of ALD in humans was associated with increased CerS6 hepatic expression. Conclusions: Our findings demonstrate that CerS6 deletion attenuates EtOH-induced weight gain and hepatic steatosis and improves glucose homeostasis in mice fed an EtOH diet. Notably, we unveil that CerS6 plays a major role as a regulator of lipid droplet biogenesis in alcoholic intra-hepatic lipid droplet formation. Together, our data suggest that CerS6 may be targeted for treatment for early stage ALD.

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Section: Discussionmentioning

confidence: 99%

Ceramide synthase 6 (CerS6) promotes alcohol-induced fatty liver by promoting metabolic dysfunction and upregulating lipid droplet-associated proteins

Jeon

Scorletti

Buyco

et al. 2022

Preprint

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“…Those findings show that leptin impacts on ceramide metabolism via malonyl‐CoA and CPT1C, and that ceramide de novo biosynthesis acts downstream of both malonyl‐CoA and CPT1C in regulating food intake and neuropeptide expression. Subsequent studies have also confirmed that dysregulation of hypothalamic de novo ceramide synthesis is a key starting point for central insulin resistance, endoplasmic reticulum stress, inflammation, and, ultimately, obesity 14,31 …”

Section: Hypothalamic Cpt1c and The Ampk‐acetyl‐coa Carboxylase (Acc)...mentioning

confidence: 92%

“…Lipid metabolism within the hypothalamus participates in this process and is a key molecular mechanism in controlling energy balance to counteract nutrient surplus 9,11,12 . There is strong evidence that a disturbance in hypothalamic lipid sensing may be partly responsible for a disrupted energy balance and the development of obesity and insulin resistance 13,14 . In fact, fatty acid (FA) sensing in hypothalamic neurons, via accumulation of long‐chain FAs or FA intermediaries, acts as a satiety signal to decrease food intake and promote energy expenditure 11,15,16 .…”

Section: Introductionmentioning

confidence: 99%

Targeting carnitine palmitoyltransferase 1 isoforms in the hypothalamus: A promising strategy to regulate energy balance

Rodríguez‐Rodríguez

Fosch

García-Chica

et al. 2023

J Neuroendocrinology

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Tackling the growing incidence and prevalence of obesity urgently requires uncovering new molecular pathways with therapeutic potential. The brain, and in particular the hypothalamus, is a major integrator of metabolic signals from peripheral tissues that regulate functions such as feeding behavior and energy expenditure. In obesity, hypothalamic capacity to sense nutritional status and regulate these functions is altered. An emerging line of research is that hypothalamic lipid metabolism plays a critical role in regulating energy balance. Here, we focus on the carnitine palmitoyltransferase 1 (CPT1) enzyme family responsible for long‐chain fatty acid metabolism. The evidence suggests that two of its isoforms expressed in the brain, CPT1A and CPT1C, play a crucial role in hypothalamic lipid metabolism, and their promise as targets in food intake and bodyweight management is currently being intensively investigated. In this review we describe and discuss the metabolic actions and potential up‐ and downstream effectors of hypothalamic CPT1 isoforms, and posit the need to develop innovative nanomedicine platforms for selective targeting of CPT1 and related nutrient sensors in specific brain areas as potential next‐generation therapy to treat obesity.

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“…Bioactive ceramides can be produced in three ways ( 6 ). First, the de novo pathway produces 3-keto-dihydrosphingosine by condensation of serine and palmitate catalyzed by serine palmityl transferase (SPT) ( 19 ). Next, sphinganine is N-acylated by six distinct ceramide synthases (CerSs) to form various dihydroceramides.…”

Section: Biosynthesis and Degradation Of Ceramidesmentioning

confidence: 99%

Role of ceramides in diabetic foot ulcers (Review)

et al. 2023

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diabetes mellitus (dM) is a metabolic disorder, which if not managed properly, can lead to serious health problems over time and impose significant financial burden on the patient, their family and society as a whole. The study of this disease and the underlying biological mechanism is gaining momentum. Multiple pieces of conclusive evidence show that ceramides are involved in the occurrence and development of diabetes. The present review focuses on the function of ceramides, a type of sphingolipid signaling molecule, to provide a brief description of ceramides and their metabolism, discuss the significant roles of ceramides in the healthy skin barrier, and speculate on the potential involvement of ceramides in the pathogenesis and development of diabetic foot ulcers (dFUs). Understanding these aspects of this disease more thoroughly is crucial to establish how ceramides contribute to the etiology of diabetic foot infections and identify possible therapeutic targets for the treatment of dFUs. Contents1. Introduction 2. Biosynthesis and degradation of ceramides 3. Ceramides in the skin 4. ceramides and dFUs 5. ceramides and vessels 6. ceramides and diabetes 7. ceramides and atherosclerosis 8. Mechanism of ceramides in diabetes 9. Mechanism of ceramides in atherosclerosis 10. Shared mechanisms between diabetic complications and dFUs 11. conclusions

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Role of hypothalamic de novo ceramides synthesis in obesity and associated metabolic disorders

Cited by 14 publications

References 96 publications

Ceramide synthase 6 (CerS6) promotes alcohol-induced fatty liver by promoting metabolic dysfunction and upregulating lipid droplet-associated proteins

Ceramide synthase 6 (CerS6) promotes alcohol-induced fatty liver by promoting metabolic dysfunction and upregulating lipid droplet-associated proteins

Targeting carnitine palmitoyltransferase 1 isoforms in the hypothalamus: A promising strategy to regulate energy balance

Role of ceramides in diabetic foot ulcers (Review)

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