Environmental regulation of metabolism : from transgenerational effects of nutrition to acute effects of exercise

The incidence of metabolic disease has risen rapidly in the last half-century leading to both individual suffering and a burden to society. The importance of physical activity for metabolic health is well known. Furthermore, there is increasing evidence that parental food choice and obesity can affect the metabolic health of future generations. Although we do not fully understand through which mechanisms these effects are occurring. Further insight into these processes can prove to be crucial in the fight against metabolic disease. Therefore, the overall aim of this thesis is to study mechanisms through which environmental interventions affect metabolic health. In study I, we investigate the skeletal muscle transcriptomic response of middle-aged men, either healthy or diagnosed with type 2 diabetes, after one bout of aerobic exercise. The two groups had a similar response to exercise just after the exercise bout. In contrast, three hours after the exercised bout skeletal muscle from diabetic subjects had an increased RNA and protein content of inflammatory markers. Thus, we describe that in skeletal muscle from subjects with type 2 diabetes there is an exacerbated inflammatory response. Whether this response is adaptive or mal-adaptive remains to be determined. In study II, we exposed male rats to a high fat diet for 10 weeks before they were bred with chow-fed females. Male F1 rats, fed a chow diet, were used to generate the F2 generation. Some of the F1 and F2 offspring were further challenged with a high fat diet. When evaluating the metabolic health of the offspring, we found that females with a high fat-fed ancestry did not gain as much body weight when they were exposed to a high fat diet themselves, but were even more glucose intolerant than their cage-mates with chow-fed ancestry. We found Let-7c to be a possible epigenetic carrier of the ancestral high fat diet. In conclusion, we provide evidence that transgenerational inheritance can cause metabolic phenotype through Let-7c. In study III and IV, we evaluated tissue-specific differences in of the transcriptome using skeletal muscle and liver from the animals in study II respectively. We used an initial transcriptomic approach and investigated the tissues with gene arrays. We found that the unfolded protein response was activated, possibly through the ATF-6 branch, in skeletal muscle from female rats with high fat fed grandfathers compared to females with a grandfather fed a chow diet, when subjugated to a high fat diet themselves. In the liver, we found that a grandpaternal high fat diet altered the TNF-α signaling pathway, independent of the offspring’s own diet. These two studies show transgenerational inheritance in specific tissues. Together, the work in this thesis highlights that effects of diet show transgenerational inheritance leading to both whole-body and tissue-specific metabolic changes. On the other hand, we show that exercise has a different response in the context of type 2 diabetes. Thus, the studies in this theses show how environmental factors can affect your metabolic health both indirectly and directly. LIST OF SCIENTIFIC PAPERS I. Alm PS, Pillon N, Arner E, Fritz T, Olsson T, Carninci P, Caidahl K, WallbergHenriksson H, Krook A, Zierath JR. Acute exercise reveals an elevated and selective inflammatory response in skeletal muscle of individuals with type 2 diabetes. Unpublished, in manuscript. II. de Castro Barbosa T, Ingerslev LR, Alm PS, Versteyhe S, Massart J, Rasmussen M, Donkin I, Sjögren R, Mudry JM, Vetterli L, Gupta S, Krook A, Zierath JR, Barrès R. High fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring. Mol Metab. 2015 Dec 25;5(3):184-197. III. Alm PS, de Castro Barbosa T, Barrès R, Krook A, Zierath JR. Grandpaternalinduced transgenerational dietary reprogramming of the unfolded protein response in skeletal muscle. Mol Metab. 2017 May 22;6(7):621-630. IV. Castro Barbosa T, Alm PS, Krook A, Barrès R, Zierath JR. Paternal high fat diet transgenerationally impacts the hepatic inflammatory response two generations later. Unpublished, in manuscript.