Intracellular and tissue specific expression of FTO protein in pig: changes with age, energy intake and metabolic status

Abstract

Genome-wide association studies in the FTO gene have identified SNPs correlating with obesity and type 2 diabetes. In mice, lack of Fto function leads to intrauterine growth retardation and lean phenotype, whereas in human it is lethal. The aim of this study in a pig model was to determine the localization of the FTO protein in different tissues and cell compartments, in order to investigate potential targets of FTO action. To better understand physiological role of FTO protein, its expression was studied in pigs of different age, metabolic status and nutrition, using both microscopic methods and Western blot analysis. For the first time, FTO protein was found in vivo in the cytoplasm, of not all, but specific tissues and cells e.g. in the pancreatic β-cells. Abundant FTO protein expression was found in the cerebellum, salivary gland and kidney of adult pigs. No FTO protein expression was detected in blood, saliva, and bile, excluding its role in cell-to-cell communication. In the pancreas, FTO protein expression was positively associated with energy intake, whereas in the muscles it was strictly agerelated. In IUGR piglets, FTO protein expression was much higher in the cerebellum and kidneys, as compared to normal birth body weight littermates. In conclusion, our data suggest that FTO protein may play a number of distinct, yet unknown intracellular functions due to its localization. Moreover, it may play a role in animal growth/development and metabolic state, although additional studies are necessary to clarify the detailed mechanism(s) of action. Genome-wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) in intron 1 of the FTO (Fat mass and obesity associated) gene are strongly correlated with an increased risk of obesity in humans 1-4. In the human FTO gene, the mutation (alteration p. Arg316 Gln) that inhibits catalytic activity of the protein, results in an autosomal recessive lethal syndrome 5. In Fto knockout mice, body weight and fat mass decrease 6 , while in animals overexpressing FTO they increase 7. Evidence from genetic epidemiology studies, life-course modeling, and diet-induced fetal programming data suggests that the FTO gene plays an important role in these complex biological interactions. It may provide the missing link in the developmental regulation of energy metabolism. The FTO variants associated with intrauterine growth retardation (IUGR) and, in consequence, low birth weight, confer a predisposition to obesity later in life. This finding favors the hypothesis of the existence of a common genetic denominator that predisposes to low birth weight and obesity in adults 8-10. Specifically, Fto deletion caused delayed growth, decreased white body fat, increased energy metabolism, and systemic sympathetic activation 6. For example, in wild-type mice, fasting reduced Fto mRNA levels and the number of Fto-immunoreactive cells in the hypothalamus. Interestingly, glucose treatment reversed this effect 11. However, another group of researchers showed that palatable ...

Ramadan Diurnal Intermittent Fasting Is Associated With Attenuated FTO Gene Expression in Subjects With Overweight and Obesity: A Prospective Cohort Study

“…Interestingly, FTO was highly expressed in the cerebellum, salivary gland, and kidney of adult pigs, whereas it was not detected in blood ( 55 ). The latter study showed FTO was positively associated with energy intake in the pancreas, and with age in the muscle, adding to the multiple factors that affect FTO expression.…”

Calmodulin as Ca2+-Dependent Interactor of FTO Dioxygenase

“…Thus, the presence of posttranslational modifications, especially serine phosphorylation [ 28 ], occurring mostly in the FTO N-terminal domain did not significantly affect FTO–CaM binding. The obtained results showing nanomolar K D are likely to be biologically relevant, because FTO in tissues occurs at nanomolar—or even lower—concentrations that can be detected by sensitive methods, such as Western blot [ 30 ]. On the other hand, total CaM concentration can be much higher.…”

Studies on the fat mass and obesity-associated (FTO) gene and its impact on obesity-associated diseases

“… 49 , 50 , 51 Recent evidence from the pig model suggested that FTO protein also existed in the cytoplasm of specific tissues and cells, e.g., in the pancreatic β-cells in a pig model. 52 Abundant FTO protein expression was also found in the cerebellum, kidney, and salivary gland of adult pigs. However, FTO protein was not detected in bile, saliva, and blood.…”

“…However, FTO protein was not detected in bile, saliva, and blood. 52 Furthermore, FTO expression in tissues relies on energy intake, metabolic status, and age, although the mechanisms governing this dependency are unknown yet. 52

Figure 3 Functional domains of the human FTO protein.

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