Fatty acid metabolism and control of food intake

Autor: Jambor de Sousa, Ulrike Leonore
Přispěvatelé: Geary, Nori, Langhans, Wolfgang
Jazyk: angličtina
Rok vydání: 2005
Předmět:
Popis: The major hypothesis for the metabolic control of eating posits that eating is inversely related to the rate of fuel oxidation. In line with this idea, blockade of fatty acidoxidation (FAO) by peripheral administration of inhibitors of FAO stimulates feeding in many species, including humans. Even though it is not proven yet that the liver is involved in this feeding-stimulatoryeffect, several findings suggest that this is the case. Yet, whether an increased hepatic FAO inhibits feeding is unknown. Therefore, the central aim of this thesis was to determine whether enhanced hepatic FAO reduces food intake. In the first study, we infused the long chain fatty acid (LCFA) oleic acid (OA) and the mediumchain fatty acid (MCFA)caprylic acid (CA) into the hepatic portal vein (HPV) of male rats to assess whether HPV infusion of these two fatty acids reducesfood intake and whether their relative efficacy differs. MCFA are oxidized faster in the liver because they are absorbed directly into the hepatic portal vein and because they can enter the mitochondria independent of the enzyme carnitine-palmitoyl-transferase1 (CPT 1). Hence, we hypothesized that HPV CA will have a greater feeding-inhibitorypotency than HPV OA. This hypothesis was not supported. Rather, 6-h HPV infusion of 14 ^ig/minOA produced a robust inhibition of feeding, whereas a dose of CA that was 14 times larger (200 jag/min) than that of OA failed to have any effect on feeding. OA (14 ^ig/min) and an 80-fold greater dose of CA (1100 ^ig/min) inhibited feeding similarly. These findings indicate that increased hepatic FAO is unlikely to be responsible for the feedinginhibitory effect of HPV OA. The plasma concentrations of the liver enzymes yglutamyltransferase (-^GT) and alanine aminotransferase (ALT), the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a), and the stress hormone corticosterone (Cort) all remained in the physiological ränge after HPV OA, indicating that liver toxicitywas also not the cause of HPV OA's potent effect on feeding. In the second study, 90-min, dark onset HPV infusion of CA (2.3 mg/min) after 18-h food-deprivation reduced the size of the first meal about 40% and reduced 24-h food intake by about 13%. The feeding-inhibitoryeffect of CA originated in the liver because identical infusions of CA into the vena cava did not affect food intake. The postprandial decreases in plasma free fatty acids (FFA) and ß-hydroxybutyrate (BHB) were attenuated in HPV CA-treated rats, indicating that hepatic FAO was increased in HPV CA infused rats relative to controls. This is consistent with the hypothesis that an increased hepatic FAO reduces food intake, but does not prove that there is a causal link between increased hepatic FAO and reduced food intake. Further the finding that animals started eating after food deprivation although their hepatic FAO was enhanced clearly demonstratesthat beside hepatic FAO other mechanismsmust be involved in the regulation of food intake. A conditioned taste aversion test was done in separate rats. Some, but not all, rats displayed aversions to saccharine paired with HPV CA infusions, but there was no significant association between the feeding-inhibitoryeffect of CA on the conditioning day and saccharine intake on the test day. Plasma concentrations of IL-6, TNF-oc, y-GT, ALT and Cort stayed at basal levels. Taken together, these data suggest that the feeding-inhibitory effect of CA was not due only to aversion or toxicity. In the third study we wanted to develop an alternative approach to test the hypothesis that increased hepatic FAO can inhibit feeding behavior. We used transgenic methods to increase the expression of CPT 1alpha, an enzyme which catalyzes the rate limiting step of hepatic FAO, in the 293T human embryonic kidney cell line. Activation of the CPTla transgenethrough an inducible tet-on gene expression system increased mitochondrial long-chain fatty acid oxidation about 6-fold. Increasing palmitic acid concentration, however, decreased viability of CPT1alpha over-expressing cells, and CPT1alpha over-expression increased cell death. These data encourage the use of this transgenic system for future in-vivo studies of the roles of fatty acid oxidation in the control of metabolism and energy balance.
Databáze: OpenAIRE
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