In vivo regulation of plasma free fatty acids in insulin resistance

Mook, Stella; Halkes, Constantijn J.M.; Bilecen, Süleyman; Cabezas, Manuel Castro

doi:10.1016/j.metabol.2004.02.023

Cited by 53 publications

(36 citation statements)

References 32 publications

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“…FFAs levels are elevated in obese individuals and may contribute to the chronic inflammatory state in obesity (9,(17)(18)(19). To determine whether moderate daily exercise with dietary control reduces FFA levels in DIO mice, we investigated their levels in LN/SCD, OB/HFD, OB/ HFD/Ex, and OB/SCD/Ex mice.…”

Section: Resultsmentioning

confidence: 99%

Signaling mechanisms in the restoration of impaired immune function due to diet-induced obesity

Zhou¹,

Leeman

Amar³

2011

Proc. Natl. Acad. Sci. U.S.A.

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Our previous data have linked obesity with immune dysfunction. It is known that physical exercise with dietary control has beneficial effects on immune function and the comorbidities of obesity. However, the mechanisms underlying the improvement of immune function in obesity after physical exercise with dietary control remain unknown. Here we show that moderate daily exercise with dietary control restores the impaired cytokine responses in dietinduced obese (DIO) mice and improves the resolution of Porphyromonas gingivalis-induced periodontitis. This restoration of immune responses is related to the reduction of circulating free fatty acids (FFAs) and TNF. Both FFAs and TNF induce an Akt inhibitor, carboxylterminal modulator protein (CTMP). The expression of CTMP is also observed increased in bone marrow-derived macrophages (BMMΦ) from DIO mice and restored after moderate daily exercise with dietary control. Toll-like receptor 2 (TLR2), which increases CTMP induction by FFAs, is inhibited in BMMΦ from DIO mice or after either FFA or TNF treatment, but unexpectedly is not restored by moderate daily exercise with dietary control. Furthermore, BMMΦ from DIO mice display reduced histone H3 (Lys-9) acetylation and NF-κB recruitment to TNF, IL-10, and TLR2 promoters after P. gingivalis infection. However, moderate daily exercise with dietary control restores these defects at promoters for TNF and IL-10, but not for TLR2. Thus, metabolizing FFAs and TNF by moderate daily exercise with dietary control improves innate immune responses to infection in DIO mice via restoration of CTMP and chromatin modification.innate immunity | bacteria clearance | Akt pathway E xcessive energy intake and sedentariness are prominent risk factors for becoming overweight and developing obesity (1, 2). Obesity is a predisposing risk factor for many health problems, including hypertension, dyslipidemia, atherosclerosis, diabetes, nonalcoholic fatty liver disease, periodontal disease, certain cancers, and asthma (3-6). Changes in immune functions have been proposed as underlying the pathogenesis of all these diseases. Obesity induces immune defects that lead to attenuated host responses to infection (7-9). The combination of dietary and exercise interventions has been proved to provide the most beneficial effects to obese people (10-12). However, few studies have addressed the molecular mechanisms involved in the restoration of obesity-induced immune defects.We previously demonstrated that diet-induced obesity (DIO) inhibited the ability of the immune system to appropriately respond to Porphyromonas gingivalis infection and concluded that this immune dysregulation participated in the increased alveolar bone loss from bacterial infections observed in DIO mice (7). Both free fatty acids (FFAs) and TNF are elevated in obesity and are important parameters for the comorbidities of obesity (13-16). FFAs activate toll-like receptor 4 (TLR4)-mediated inflammatory signaling pathways and induce TNF expression in DIO mice (16).In contrast, TLR2, which ne...

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Section: Resultsmentioning

confidence: 99%

Signaling mechanisms in the restoration of impaired immune function due to diet-induced obesity

Zhou¹,

Leeman

Amar³

2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Plasma concentrations of free FA are increased in conditions of metabolic syndrome, that includes hypertension, 28 obesity 29 and diabetes. 30,31 Some FA are known to have a potent immunosuppressor effect, 17,32,33 but it is not clear if this effect is due to the toxicity of these FA.…”

Section: Introductionmentioning

confidence: 99%

Regulation of human lymphocyte proliferation by fatty acids

Gorjão

Cury-Boaventura

Lima

et al. 2006

Cell Biochemistry & Function

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In the present study, the effect of increasing concentrations of palmitic (PA, C16:0), stearic (SA, C18:0), oleic (OA, C18:1, n-9), linoleic (LA, C18:2n-6), docosahexaenoic (DHA, C22:6 n-3) and eicosapentaenoic (EPA, C20:5 n-3) acids on lymphocyte proliferation was investigated. The maximal non-toxic concentrations of these fatty acids for human lymphocytes in vitro were determined. It was also evaluated whether these fatty acids at non-toxic concentrations affect IL-2 induced lymphocyte proliferation and cell cycle progression. OA and LA at 25 microM increased lymphocyte proliferation and at higher concentrations (75 microM and 100 microM) inhibited it. Both fatty acids promoted cell death at 200 microM concentration. PA and SA decreased lymphocyte proliferation at 50 microM and promoted cell death at concentrations of 100 microM and above. EPA and DHA decreased lymphocyte proliferation at 25 and 50 microM being toxic at 50 and 100 microM, respectively. PA, SA, DHA and EPA decreased the stimulatory effect of IL-2 on lymphocyte proliferation, increasing the percentage of cells in G1 phase and decreasing the proportion of cells in S and G2/M phases. OA and LA caused an even greater pronounced effect. The treatment with all fatty acids increased neutral lipid accumulation in the cells but the effect was more pronounced with PA and DHA. In conclusion, PA, SA, DHA and EPA decreased lymphocyte proliferation, whereas OA and LA stimulated it at non-toxic concentrations.

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“…In patients with type 2 diabetes, NEFA concentrations are typically 50-100% higher, in the 500-800 mol/l range ( 57,58 ). Similar elevations are observed in nondiabetic, insulin-resistant patients ( 59 ). TZD PPAR-␥ activators are among the most effective available pharmacologic agents to reduce plasma NEFA concentrations, with effects similar in magnitude to therapeutic doses of insulin ( 60 ).…”

Section: Blood Pressurementioning

confidence: 85%