Long chain saturated and unsaturated fatty acids exert opposing effects on viability and function of GLP-1-producing cells: Mechanisms of lipotoxicity

Thombare, Ketan; Ntika, Stelia; Wang, X; Krizhanovskii, Camilla

doi:10.1371/journal.pone.0177605

Cited by 23 publications

(18 citation statements)

References 41 publications

(47 reference statements)

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“…L-cell dysfunction has been reported in the DIO models for the GLP-1 reduction 3 – 5 . Although LCFAs have been reported to inhibit L-cell function through induction of endoplasmic reticulum stress or cell apoptosis 23 , 24 , the mitochondrial response in the L-cell dysfunction remains unknown. Our data suggest that the L-cell dysfunction is associated with mitochondrial stress responses.…”

Section: Discussionmentioning

confidence: 99%

Restoration of GLP-1 secretion by Berberine is associated with protection of colon enterocytes from mitochondrial overheating in diet-induced obese mice

et al. 2018

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ObjectiveL-cell dysfunction is reported for GLP-1 reduction in type 2 diabetes. However, the mechanism of dysfunction remains unknown. In this study, we examined mitochondrial function in the mechanistic study in diet-induced obese (DIO) mice.SubjectsC57BL/6 mice were fed a high-fat diet (HFD) for 16 weeks to establish the DIO model for GLP-1 reduction. The mice were then treated with berberine (BBR) (100 mg/kg/day) for 8 weeks to test the impact on GLP-1 expression. Mitochondrial activities of the colon enterocytes were compared among three groups of mice (lean, DIO, and DIO + BBR) at the end of treatment. Gut microbiota and short-chain fatty acids (SCFAs) were examined to understand the mitochondrial responses. A cellular model treated with palmitic acid (PA) was used in the mechanism study.ResultsA reduction in GLP-1 expression was observed in DIO mice with mitochondrial stress responses in the colon enterocytes. The mitochondria exhibited cristae loss, membrane rupture, and mitochondrial swelling, which was observed with an increase in ATP abundance, complex I activity, and deficiency in the activities of complexes II and IV. Those changes were associated with dysbiosis and a reduction in SCFAs in the colon of DIO mice. In the cellular model, an increase in ATP abundance, loss of mitochondrial potential, and elevation of apoptosis were induced by PA. All of the alterations in DIO mice and the cellular model were attenuated by BBR.ConclusionThe mitochondrial stress responses were observed in the colon enterocytes of DIO mice for GLP-1 reduction. The stress was prevented by BBR in the restoration of GLP-1 expression, in which BBR may act through direct and indirect mechanisms.

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Section: Discussionmentioning

confidence: 99%

Restoration of GLP-1 secretion by Berberine is associated with protection of colon enterocytes from mitochondrial overheating in diet-induced obese mice

et al. 2018

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“…We divided FAs into saturated FAs (SFAs) and unsaturated FAs (UFAs) because of their different biological functions. 28 In our previous study, the decrease of saturated FA content was an important lipid marker for the weakening of skin barrier function, while the increase of unsaturated FA content was an important lipid marker for the destruction of skin barrier function. 29 In addition, although the contents of glycerolphospholipids (GPs) and ceramides (Cers) did not show a trend change, it is worth noting that both GPs and Cers have a positive effect on skin barrier function.…”

Section: The a Sso Ciati On B E T Ween The Effec T Of S E X Hormone S On S Ebum And S K In Cond Iti Onmentioning

confidence: 87%

Lipidomics demonstrates the association of sex hormones with sebum

Chen

et al. 2021

J of Cosmetic Dermatology

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Sex hormones are divided into androgen and estrogen, which can directly or indirectly regulate the activity of sebaceous glands. Among them, testosterone (T) and dihydrotestosterone (DHT) are most biologically active in androgens. After binding to androgen receptor in the basal layer of sebocytes, the excessive increment and sebum production of sebum cells are promoted by synergistic action with PPAR ligands. 1,2 However, estrogen does not directly affect the activity of sebocytes, but can achieve indirect effects by inhibiting androgen regulation of sebocytes. 3 For example, progesterone can block androgen receptors and inhibit the activity of free androgen in vivo. Estradiol can reduce the level of androgens with bio-active by up-regulating the level of sex hormone-binding globulin. 4 Therefore, sex hormones do have a crucial effect on sebocytes. Importantly, we also supported this by qualitative analysis in the changes of skin surface lipid (SSL) content and composition in people with different sex hormone levels through lipidomics.Lipidomics can conduct a comprehensive and systematic analysis of lipids, reveal the relationship between lipids and cells, organs, and bodies in physiology and pathology by identifying the structure and function of lipids. 5 In the past few years, we used lipidomics (Ultra Performance Liquid Chromatography-Quadrupole Time-of-Flight-Mass Spectrometer, UPLC-QTOF-MS) to analyze the important role of lipids in different skin conditions. [6][7][8][9][10] Including acne vulgaris, sensitive muscles, etc., we found significant differences in SSL in different skin conditions. [10][11][12] Importantly, when we studied the SSL of young men and women and middle-pregnancy women (without obvious skin diseases), we stumbled upon potential consistency in their lipid changes. Through literature research and data analysis, we found that this phenomenon may be related to the level of sex hormones in the body. 13 The regulation of sebocytes by sex hormones leads to the change of sebum. 14 Therefore, this paper focuses on sex hormones and sebum, in order to reveal the important association of sex hormones on sebum.

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“…Importantly, when reviewing the literature, we found a lack of in vitro and in vivo studies showing the assessment of ceramide levels in response to unsaturated fatty acids such as palmitoleate or EPA/DHA. For instance, the authors of [99] used GLP-1-secreting GLUTag cells and found that PA (C16:0) but not palmitoleate (PO, C16:1) induces ceramide production, whereas unsaturated fatty acids confer lipoprotection by enhancing cell viability. Additionally, unsaturated fatty acids can ameliorate inflammation triggered by palmitate [79,100,101]; therefore, it is possible that they can decrease ceramide levels or at least reverse the effects of ceramide.…”

Section: Discussionmentioning

confidence: 99%

The Role of Fatty Acids in Ceramide Pathways and Their Influence on Hypothalamic Regulation of Energy Balance: A Systematic Review

Reginato

Verás

Baqueiro

et al. 2021

IJMS

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Obesity is a global health issue for which no major effective treatments have been well established. High-fat diet consumption is closely related to the development of obesity because it negatively modulates the hypothalamic control of food intake due to metaflammation and lipotoxicity. The use of animal models, such as rodents, in conjunction with in vitro models of hypothalamic cells, can enhance the understanding of hypothalamic functions related to the control of energy balance, thereby providing knowledge about the impact of diet on the hypothalamus, in addition to targets for the development of new drugs that can be used in humans to decrease body weight. Recently, sphingolipids were described as having a lipotoxic effect in peripheral tissues and the central nervous system. Specifically, lipid overload, mainly from long-chain saturated fatty acids, such as palmitate, leads to excessive ceramide levels that can be sensed by the hypothalamus, triggering the dysregulation of energy balance control. However, no systematic review has been undertaken regarding studies of sphingolipids, particularly ceramide and sphingosine-1-phosphate (S1P), the hypothalamus, and obesity. This review confirms that ceramides are associated with hypothalamic dysfunction in response to metaflammation, endoplasmic reticulum (ER) stress, and lipotoxicity, leading to insulin/leptin resistance. However, in contrast to ceramide, S1P appears to be a central satiety factor in the hypothalamus. Thus, our work describes current evidence related to sphingolipids and their role in hypothalamic energy balance control. Hypothetically, the manipulation of sphingolipid levels could be useful in enabling clinicians to treat obesity, particularly by decreasing ceramide levels and the inflammation/endoplasmic reticulum stress induced in response to overfeeding with saturated fatty acids.

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Long chain saturated and unsaturated fatty acids exert opposing effects on viability and function of GLP-1-producing cells: Mechanisms of lipotoxicity

Cited by 23 publications

References 41 publications

Restoration of GLP-1 secretion by Berberine is associated with protection of colon enterocytes from mitochondrial overheating in diet-induced obese mice

Restoration of GLP-1 secretion by Berberine is associated with protection of colon enterocytes from mitochondrial overheating in diet-induced obese mice

Lipidomics demonstrates the association of sex hormones with sebum

The Role of Fatty Acids in Ceramide Pathways and Their Influence on Hypothalamic Regulation of Energy Balance: A Systematic Review

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