Opposite Cross-Talk by Oleate and Palmitate on Insulin Signaling in Hepatocytes through Macrophage Activation

Pardo, Virginia; González-Rodrı́guez, Águeda; Guijas, Carlos; Balsinde, Jesús; Valverde, Ángela M.

doi:10.1074/jbc.m115.649483

Cited by 48 publications

(49 citation statements)

References 77 publications

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“…Because the initial differences among cocultures existed solely in macrophages (e.g., the presence or absence of A 2A R), the outcomes of hepatocyte lipogenic events were attributable to the effects secondary to A 2A R disruption‐associated increase in macrophage proinflammatory activation. The latter has been shown to generate macrophage‐derived factors (i.e., proinflammatory cytokines) to promote hepatocyte lipogenic events, enhance hepatocyte proinflammatory responses, and decrease hepatocyte insulin signaling . Therefore, the results from myeloid cell–specific A 2A R‐deficient mice and macrophage–hepatocyte cocultures demonstrate that A 2A R has a role in coordinating macrophage actions on hepatocytes to protect against NAFLD aspects.…”

Section: Discussionmentioning

confidence: 99%

Disruption of adenosine 2A receptor exacerbates NAFLD through increasing inflammatory responses and SREBP1c activity

Cai

et al. 2018

Hepatology

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Section: Discussionmentioning

confidence: 99%

Disruption of adenosine 2A receptor exacerbates NAFLD through increasing inflammatory responses and SREBP1c activity

Cai

et al. 2018

Hepatology

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“…Death of adipocytes from oleate accumulation is unlikely, because unsaturated fatty acids are not considered lipotoxic toward these cells 38, 39. Unsaturated fatty acids are also relatively weak activators of macrophages40, 41, 42; thus, the link between oleate and adipose tissue necrosis and inflammation is likely indirect. Oleate could induce an immune response indirectly in adipose tissue by covalently modifying adipocyte proteins to generate neoantigens 43, 44.…”

Section: Discussionmentioning

confidence: 99%

Specific Macronutrients Exert Unique Influences on the Adipose-Liver Axis to Promote Hepatic Steatosis in Mice

Duwaerts

Amin

Siao

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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Background & AimsThe factors that distinguish metabolically healthy obesity from metabolically unhealthy obesity are not well understood. Diet has been implicated as a determinant of the unhealthy obesity phenotype, but which aspects of the diet induce dysmetabolism are unknown. The goal of this study was to investigate whether specific macronutrients or macronutrient combinations provoke dysmetabolism in the context of isocaloric, high-energy diets.MethodsMice were fed 4 high-energy diets identical in calorie and nutrient content but different in nutrient composition for 3 weeks to 6 months. The test diets contained 42% carbohydrate (sucrose or starch) and 42% fat (oleate or palmitate). Weight and glucose tolerance were monitored; blood and tissues were collected for histology, gene expression, and immunophenotyping.ResultsMice gained weight on all 4 test diets but differed significantly in other metabolic outcomes. Animals fed the starch-oleate diet developed more severe hepatic steatosis than those on other formulas. Stable isotope incorporation showed that the excess hepatic steatosis in starch-oleate–fed mice derived from exaggerated adipose tissue lipolysis. In these mice, adipose tissue lipolysis coincided with adipocyte necrosis and inflammation. Notably, the liver and adipose tissue abnormalities provoked by starch-oleate feeding were reproduced when mice were fed a mixed-nutrient Western diet with 42% carbohydrate and 42% fat.ConclusionsThe macronutrient composition of the diet exerts a significant influence on metabolic outcome, independent of calories and nutrient proportions. Starch-oleate appears to cause hepatic steatosis by inducing progressive adipose tissue injury. Starch-oleate phenocopies the effect of a Western diet; consequently, it may provide clues to the mechanism whereby specific nutrients cause metabolically unhealthy obesity.

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“…In particular, elevated levels of SFAs induce inflammation, which results in insulin resistance via several pathways involving diacylglycerol-mediated protein kinase C activation or Toll-like receptors[38–39]. On the other hand, data are emerging which support that monounsaturated fatty acids have protective effects against saturated fat mediated toxicity[38–40]. Moreover, cultured cells incubated in high concentrations of saturated fatty acids exhibited impaired insulin signaling[41].…”

Section: Discussionmentioning

confidence: 99%

Chronic Olanzapine Treatment Induces Disorders of Plasma Fatty Acid Profile in Balb/c Mice: A Potential Mechanism for Olanzapine-Induced Insulin Resistance

Li¹,

Fang²,

Xu³

et al. 2016

PLoS ONE

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BackgroundAtypical antipsychotics such as olanzapine cause metabolic side effects leading to obesity and insulin resistance. The underlying mechanisms remain elusive. In this study we investigated the effects of chronic treatment of olanzapine on the fatty acid composition of plasma in mice.MethodsTwenty 8-week female Balb/c mice were randomly assigned to two groups: the OLA group and the control group. After treatment with olanzapine (10 mg/kg/day) or vehicle intraperitoneally for 8 weeks, fasting glucose, insulin levels and oral glucose tolerance test were determined. Effects on plasma fatty acid profile and plasma indices of D5 desaturase, D6 desaturase and SCD1 activity were also investigated.ResultsChronic administration of olanzapine significantly elevated fasting glucose and insulin levels, impaired glucose tolerance, but did not increase body weight. Total saturated fatty acids and n-6 polyunsaturated fatty acids were significantly increased and total monounsaturated fatty acids were significantly decreased, while total n-3 polyunsaturated fatty acids showed no prominent changes. Chronic olanzapine treatment significantly up-regulated D6 desaturase activity while down-regulating D5 desaturase activity. Palmitic acid (C16:0), dihomo-γ-linolenic acid (C20:3n-6) and D6 desaturase were associated with an increase probability of insulin resistance, whereas nervonic acid (C24:1) and SCD1 were significantly associated with a lower insulin resistance probability.ConclusionsAll results indicated that such drug-induced effects on fatty acid profile in plasma were relevant for the metabolic adverse effects associated with olanzapine and possibly other antipsychotics. Further studies are needed to investigate geneticand other mechanisms to explain how plasma fatty acids regulate glucose metabolism and affect the risk of insulin resistance.

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Opposite Cross-Talk by Oleate and Palmitate on Insulin Signaling in Hepatocytes through Macrophage Activation

Cited by 48 publications

References 77 publications

Disruption of adenosine 2A receptor exacerbates NAFLD through increasing inflammatory responses and SREBP1c activity

Disruption of adenosine 2A receptor exacerbates NAFLD through increasing inflammatory responses and SREBP1c activity

Specific Macronutrients Exert Unique Influences on the Adipose-Liver Axis to Promote Hepatic Steatosis in Mice

Chronic Olanzapine Treatment Induces Disorders of Plasma Fatty Acid Profile in Balb/c Mice: A Potential Mechanism for Olanzapine-Induced Insulin Resistance

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