Cultured hypothalamic neurons are resistant to inflammation and insulin resistance induced by saturated fatty acids

Choi, Sukjin; Kim, Francis; Schwartz, Michael W.; Wisse, Brent E.

doi:10.1152/ajpendo.00006.2010

Cited by 65 publications

(53 citation statements)

References 26 publications

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“…The combination of results suggests that monocytes are more responsive to palmitate expressing TNFa, whereas the neuron cell line is more responsive to TNFa producing fractalkine and other inflammatory markers. This observation is in accordance with a previous study (11) and suggests that neurons are not the primary targets for dietary fats, which are affected only after glial cells are engaged, as previously proposed (6).…”

Section: Discussionsupporting

confidence: 93%

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Fractalkine (CX3CL1) Is Involved in the Early Activation of Hypothalamic Inflammation in Experimental Obesity

et al. 2014

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Hypothalamic inflammation is a common feature of experimental obesity. Dietary fats are important triggers of this process, inducing the activation of toll-like receptor-4 (TLR4) signaling and endoplasmic reticulum stress. Microglia cells, which are the cellular components of the innate immune system in the brain, are expected to play a role in the early activation of diet-induced hypothalamic inflammation. Here, we use bone marrow transplants to generate mice chimeras that express a functional TLR4 in the entire body except in bone marrow–derived cells or only in bone marrow–derived cells. We show that a functional TLR4 in bone marrow–derived cells is required for the complete expression of the diet-induced obese phenotype and for the perpetuation of inflammation in the hypothalamus. In an obesity-prone mouse strain, the chemokine CX3CL1 (fractalkine) is rapidly induced in the neurons of the hypothalamus after the introduction of a high-fat diet. The inhibition of hypothalamic fractalkine reduces diet-induced hypothalamic inflammation and the recruitment of bone marrow–derived monocytic cells to the hypothalamus; in addition, this inhibition reduces obesity and protects against diet-induced glucose intolerance. Thus, fractalkine is an important player in the early induction of diet-induced hypothalamic inflammation, and its inhibition impairs the induction of the obese and glucose intolerance phenotypes.

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Section: Discussionsupporting

confidence: 93%

“…In at least one study, hypothalamic neurons were unable to respond to palmitate-producing cytokines (11). Thus, glial cells, particularly microglia, may be an important requirement of the system.…”

mentioning

confidence: 99%

Fractalkine (CX3CL1) Is Involved in the Early Activation of Hypothalamic Inflammation in Experimental Obesity

et al. 2014

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“…The evaluation of insulin receptor signaling was done as described previously (9). Briefly, mouse liver (AML12; ATCC CRL-2254) and myoblast (C 2C12; CRL-1772) cell lines were cultured in Dulbecco's modified Eagle's medium (Gibco-Invitrogen, Carlsbad, CA) containing 10% fetal bovine serum (Hyclone, Logan, UT), 2 mM glutamine, nonessential amino acid, and penicillin-streptomycin and maintained at 37°C in 5% CO 2.…”

Section: Methodsmentioning

confidence: 99%

Deficiency of lymphotoxin-α does not exacerbate high-fat diet-induced obesity but does enhance inflammation in mice

Pamir

McMillen

Edgel

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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(LT␣) is secreted by lymphocytes and acts through tumor necrosis factor-␣ receptors and the LT␤ receptor. Our goals were to determine whether LT has a role in obesity and investigate whether LT contributes to the link between obesity and adipose tissue lymphocyte accumulation. LT deficient (LT Ϫ/Ϫ ) and wild-type (WT) mice were fed standard pelleted rodent chow or a high-fat/high-sucrose diet (HFHS) for 13 wk. Body weight, body composition, and food intake were measured. Glucose tolerance was assessed. Systemic and adipose tissue inflammatory statuses were evaluated by quantifying plasma adipokine levels and tissue macrophage and T cell-specific gene expression in abdominal fat. LT Ϫ/Ϫ mice were smaller (20%) and leaner (25%) than WT controls after 13 wk of HFHS diet feeding. LT Ϫ/Ϫ mice showed improved glucose tolerance, suggesting that, in WT mice, LT may impair glucose metabolism. Surprisingly, adipose tissue from rodent chow-and HFHS-fed LT Ϫ/Ϫ mice exhibited increased T lymphocyte and macrophage infiltration compared with WT mice. Despite the fact that LT Ϫ/Ϫ mice exhibited an enhanced inflammatory status at the systemic and tissue level even when fed rodent chow, they were protected from enhanced diet-induced obesity and insulin resistance. Thus, LT contributes to body weight and adiposity and is required to modulate the accumulation of immune cells in adipose tissue.

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“…The hypothalamus has an emerging role in the regulation of hepatic glucose efflux, and SFAs have been shown to promote central leptin and insulin resistance associated with reduced activation of the anabolic enzyme Akt/protein kinase B (21)(22)(23)(24). Lipid infusion significantly increased hypothalamic ceramide content of WT mice ( Figure 4C).…”

Section: Figurementioning

confidence: 98%

Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid–induced ceramide biosynthesis in mice

et al. 2011

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Obesity is associated with an enhanced inflammatory response that exacerbates insulin resistance and contributes to diabetes, atherosclerosis, and cardiovascular disease. One mechanism accounting for the increased inflammation associated with obesity is activation of the innate immune signaling pathway triggered by TLR4 recognition of saturated fatty acids, an event that is essential for lipid-induced insulin resistance. Using in vitro and in vivo systems to model lipid induction of TLR4-dependent inflammatory events in rodents, we show here that TLR4 is an upstream signaling component required for saturated fatty acid-induced ceramide biosynthesis. This increase in ceramide production was associated with the upregulation of genes driving ceramide biosynthesis, an event dependent of the activity of the proinflammatory kinase IKKβ. Importantly, increased ceramide production was not required for TLR4-dependent induction of inflammatory cytokines, but it was essential for TLR4-dependent insulin resistance. These findings suggest that sphingolipids such as ceramide might be key components of the signaling networks that link lipid-induced inflammatory pathways to the antagonism of insulin action that contributes to diabetes.

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Cultured hypothalamic neurons are resistant to inflammation and insulin resistance induced by saturated fatty acids

Cited by 65 publications

References 26 publications

Fractalkine (CX3CL1) Is Involved in the Early Activation of Hypothalamic Inflammation in Experimental Obesity

Fractalkine (CX3CL1) Is Involved in the Early Activation of Hypothalamic Inflammation in Experimental Obesity

Deficiency of lymphotoxin-α does not exacerbate high-fat diet-induced obesity but does enhance inflammation in mice

Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid–induced ceramide biosynthesis in mice

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