Regulation of body energy homeostasis by the selected retinoids and fatty acids

Abstract

Beside their general effects on satiety, ingested nutrients affect body control mechanisms that regulate energy balance and that include different processes involved in the control of food intake, energy expenditure and local tissue processes. Fatty acids (FA) and vitamin A related compounds are both nutrients with lipidic nature and already known to exert different effects on these processes. It is known that FAs are the ones responsible for the trigliceride effects in the central nervous system as well as in the gastrointestinal tract. Similarly vitamin A metabolites are higly active compounds required for a wide range of biological processes. However, due to the great variety of FA structures and their physicochemical properties as well as a number of vitamin A metabolites there are still many gaps in our knowledge on their effects, especially with regard to the underlying molecular mechanism. Thus, the general objective of this thesis was to study into more depth the effects of these two groups of nutrients on the processes involved in the body energy homeostasis and to profound the understanding of their molecular mechanisms. The first line of the thesis dealt with the FA effects on food intake. More further on, it revolved around the different satiating capacities of the long-chain saturated palmitic fatty acid and the unsaturated linoleic fatty acid. In particular, we were interested to explain the observed satiety differences through: a) FA central effects on the hipothalamic gene expression and the levels of neuropeptides involved in the short- term control of food intake, and b) FA gastrointestinal effects on the stomach protein expression and secretion. Special attention was given to stomach hormones leptin and ghrelin that are involved in the short-term control of satiety and hunger, respectively. The second line of the thesis dealing with the vitamin A metabolites had as an objective to investigate their effects on body energy expenditure and local tissue processes especially the ones associated with the biology and function of adipose tissue. In particular we explored: a) the effects of early vitamin A supplementation (in the form of retynil ester, RE) on the white adipose tissue (WAT) development and its consequences on the later propensity to obesity, b) effects of H-carotene on adipose tissue biology in the same life period, during lactation c) effects of all-trans retinoic acid (ATRA) on skeletal muscle secretoma, possible to have direct effects on adipose tissue and as such being another mechanism likely contributing to ATRA activation of WAT, and d) ATRA effects on mitochondriogenesis and the induction of WAT oxidative metabolism and thermogenesis in relation to ATRA induced process of browning. The results obtained inside the first line show different satiating capacities of palmitic and linoleic acid, which can be explained by their distinctive central effects affecting the expression of hypothalamic neuropeptides included in the control of food intake as well as distinct gastrointestinal effects, including gastrointestinal hormone expression and release. In concrete, stronger satiating capacities of linoleic acid could 14 be explained by its earlier and stronger activation of anorexigenic signalling in the hipotalamus as well as the decrease in ghrelin levels. However, in addition to these already known effects of ghrelin, our results point out the role of gastric leptin in the FA satiating action and indicate a possibility of this being a safety mechanism to counteract anorexigenic central actions induced by FFAs via inhibition of gastric ghrelin, especially in stress situations such as fasting. Results from the second line of investigation regarding vitamin A early supplementation on WAT development indicate that such supplementation (as RE) affects adipose cells to retain increased proliferation potential (higher expression of PCNA), which correlated with a reduced expression of adipogenic markers (e.g. PPARI). These changes facilitate fat storage and thus favor the increased adiposity gain upon a subsequent stimulus in the form of a high fat diet later in life, which was observed previously by our group. On the other hand, although its absorption was confirmed by significantly increased serum and liver levels, H-carotene supplementation in the same period did not affect adipose tissue development in young rats. In fact, H- carotene in the iWAT of these animals was not even detected. Furthermore in the same line of investigation, results of the ATRA treatments showed affected myokine production in the skeletal muscle cells, e.g. induced expression of FNDC5/irisin and FGF21, which were proved to exert effects upon adipose tissue, including browning. These changes in skeletal muscle contribute to the understanding of ATRA anti-obesity and anti-diabetic action and the enhancement of whole body fatty acid catabolism. Additionaly in the same line, our results indicate that ATRA induces mitochondria biogenesis and oxidative phosphorylation/thermogenic capacities in mature white adipocytes. This impact of ATRA could explain the possible remodeling of mature white adipocytes into mitochondria-rich more brown-fat like cells, described previously by our group. Taken together, these results show various effects of fatty acids and vitamin A metabolites on different body control processes that contribute to the organism’s energy homeostasis. Knowledge of FA effects with regard to the food intake can broaden our understanding of the metabolic effects of different diets and their effects on body weight control as well as open up possibilities for the design of new fat replacers with improved efficiency. Vitamin A research is a broad area each time showing more proofs of the importance of related nutrients in the adipose tissue biology and with this associated control of body weight. Results presented here contribute to the understanding of their effects on different tissue processes and the elements of energy expenditure that could be used in the prevention and treatment of obesity and associated metabolic disorders.