RESUMO
Dietary polyunsaturated fatty acids (PUFA) are increasingly recognized for their health benefits, whereas a high production of endogenous fatty acids - a process called de novo lipogenesis (DNL) - is closely linked to metabolic diseases. Determinants of PUFA incorporation into complex lipids are insufficiently understood and may influence the onset and progression of metabolic diseases. Here we show that fatty acid synthase (FASN), the key enzyme of DNL, critically determines the use of dietary PUFA in mice and humans. Moreover, the combination of FASN inhibition and PUFA-supplementation decreases liver triacylglycerols (TAG) in mice fed with high-fat diet. Mechanistically, FASN inhibition causes higher PUFA uptake via the lysophosphatidylcholine transporter MFSD2A, and a diacylglycerol O-acyltransferase 2 (DGAT2)-dependent incorporation of PUFA into TAG. Overall, the outcome of PUFA supplementation may depend on the degree of endogenous DNL and combining PUFA supplementation and FASN inhibition might be a promising approach to target metabolic disease.
Assuntos
Ácidos Graxos Ômega-3 , Doenças Metabólicas , Camundongos , Humanos , Animais , Lipogênese , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Insaturados , Triglicerídeos/metabolismo , Ácidos Graxos , Dieta Hiperlipídica/efeitos adversosRESUMO
The omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) is implicated in theregulation of both lipid and carbohydrate metabolism. Thus, we questioned whether dietary DHAand low or high content of sucrose impact on metabolism in mice deficient for elongation of verylong-chain fatty acids 2 (ELOVL2), an enzyme involved in the endogenous DHA synthesis. Wefound that Elovl2 -/- mice fed a high-sucrose DHA-enriched diet followed by the high sucrose, highfat challenge significantly increased body weight. This diet affected the triglyceride rich lipoproteinfraction of plasma lipoproteins and changed the expression of several genes involved in lipidmetabolism in a white adipose tissue. Our findings suggest that lipogenesis in mammals issynergistically influenced by DHA dietary and sucrose content.
Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Sacarose Alimentar/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Lipogênese/efeitos dos fármacos , Aumento de Peso/efeitos dos fármacos , Acetiltransferases/genética , Acetiltransferases/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Dieta Hiperlipídica , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/sangue , Ácidos Docosa-Hexaenoicos/deficiência , Elongases de Ácidos Graxos , Lipogênese/genética , Lipoproteínas/sangue , Camundongos Knockout , Triglicerídeos/sangueRESUMO
Docosahexaenoic acid (DHA) is an omega-3 fatty acid obtained from the diet or synthesized from alpha-linolenic acid through the action of fatty acid elongases (ELOVL) and desaturases. DHA plays important roles in the central nervous system as well as in peripheral organs and is the precursor of several molecules that regulate resolution of inflammation. In the present study, we questioned whether impaired synthesis of DHA affected macrophage plasticity and polarization both in vitro and in vivo models. For this we investigated the activation status and inflammatory response of bone marrow-derived M1 and M2 macrophages obtained from mice deficient of Elovl2 (Elovl2-/-), a key enzyme for DHA synthesis in mammals. Although both wild type and Elovl2-/- mice were able to generate efficient M1 and M2 macrophages, M1 cells derived from Elovl2-/- mice showed an increased expression of key markers (iNOS, CD86 and MARCO) and cytokines (IL-6, IL-12 and IL-23). However, M2 macrophages exhibited upregulated M1-like markers like CD80, CD86 and IL-6, concomitantly with a downregulation of their signature marker CD206. These effects were counteracted in cells obtained from DHA-supplemented animals. Finally, white adipose tissue of Elovl2-/- mice presented an M1-like pro-inflammatory phenotype. Hence, impairment of systemic DHA synthesis delineates an alteration of M1/M2 macrophages both in vitro and in vivo, with M1 being hyperactive and more pro-inflammatory while M2 less protective, supporting the view that DHA has a key role in controlling the balance between pro- and anti-inflammatory processes.
Assuntos
Ácidos Docosa-Hexaenoicos/imunologia , Inflamação/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/imunologia , Animais , Polaridade Celular/efeitos dos fármacos , Células Cultivadas , Ácidos Docosa-Hexaenoicos/farmacologia , Inflamação/tratamento farmacológico , Interleucina-12/imunologia , Interleucina-23/imunologia , Interleucina-6/imunologia , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/imunologiaRESUMO
FGF21 decreases plasma triglycerides (TGs) in rodents and humans; however, the underlying mechanism or mechanisms are unclear. In the present study, we examined the role of FGF21 in production and disposal of TG-rich lipoproteins (TRLs) in mice. Treatment with pharmacological doses of FGF21 acutely reduced plasma non-esterified fatty acids (NEFAs), liver TG content, and VLDL-TG secretion. In addition, metabolic turnover studies revealed that FGF21 facilitated the catabolism of TRL in white adipose tissue (WAT) and brown adipose tissue (BAT). FGF21-dependent TRL processing was strongly attenuated in CD36-deficient mice and transgenic mice lacking lipoprotein lipase in adipose tissues. Insulin resistance in diet-induced obese and ob/ob mice shifted FGF21 responses from WAT toward energy-combusting BAT. In conclusion, FGF21 lowers plasma TGs through a dual mechanism: first, by reducing NEFA plasma levels and consequently hepatic VLDL lipidation and, second, by increasing CD36 and LPL-dependent TRL disposal in WAT and BAT.
Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Fatores de Crescimento de Fibroblastos/farmacologia , Hipolipemiantes/farmacologia , Lipoproteínas VLDL/metabolismo , Triglicerídeos/sangue , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Feminino , Fatores de Crescimento de Fibroblastos/uso terapêutico , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hipolipemiantes/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Obesity is characterized by a positive energy balance and expansion of white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) combusts energy to produce heat. Here we show that a small molecule stimulator (BAY 41-8543) of soluble guanylyl cyclase (sGC), which produces the second messenger cyclic GMP (cGMP), protects against diet-induced weight gain, induces weight loss in established obesity, and also improves the diabetic phenotype. Mechanistically, the haeme-dependent sGC stimulator BAY 41-8543 enhances lipid uptake into BAT and increases whole-body energy expenditure, whereas ablation of the haeme-containing ß1-subunit of sGC severely impairs BAT function. Notably, the sGC stimulator enhances differentiation of human brown adipocytes as well as induces 'browning' of primary white adipocytes. Taken together, our data suggest that sGC is a potential pharmacological target for the treatment of obesity and its comorbidities.