Biology subjects

Savary, L.

Publications and source records attributed to Savary, L..

6 recordsLinked to original sources

bioRxiv2024

Shared genetic architecture links energy metabolism, behavior and starvation resistance along a power-endurance axis

Shared developmental, physiological and molecular mechanisms can generate strong genetic covariances across suites of traits, constraining genetic variability and evolvability to certain axes in multivariate trait space ("variational modules" or "syndromes"). Such trait suites will not only respond jointly to selection; they will also covary across populations that diverged from one another by genetic drift. We report evidence for such a genetically correlated trait suite in Drosophila melanogaster. It links high expression of glycolysis and TCA cycle genes, high abundance of mitochondria and high spontaneous locomotor activity with low degree of adiposity, and low endurance and early death under starvation. This "power-endurance" axis is also aligned with abundance of certain metabolites, notably low trehalose (blood sugar) and high levels of some amino acids and their derivatives, including creatine, a compound known to facilitate energy production in muscles. Our evidence comes from six replicate "Selected" populations adapted to a nutrient-poor larval diet regime during 250 generations of experimental evolution and six "Control" populations evolved in parallel on a standard diet regime. We found that, within each of these experimental evolutionary regime, the above traits strongly covaried along the power-endurance axis across replicate populations which diversified by drift, indicating a shared genetic architecture. The two evolutionary regimes also drove divergence along this axis, with Selected populations on average displaced towards the "power" direction compared to Controls. Aspects of this "power-endurance" axis resemble the "pace of life" syndrome and the "thrifty phenotype"; it may have evolved as part of a coordinated organismal response to nutritional conditions.

evolutionary biology↗

bioRxiv2023

Cis-regulatory polymorphism at fiz ecdysone oxidase contributes to polygenic adaptation to malnutrition in Drosophila

We investigate the contribution of a candidate gene, fiz (fezzik), to complex polygenic adaptation to juvenile malnutrition in Drosophila melanogaster. We show that experimental populations adapted during >250 generations of experimental evolution to a nutritionally poor larval diet (Selected populations) evolved several-fold lower fiz expression compared to unselected Control populations. This divergence in fiz expression is mediated by a cis-regulatory polymorphism. This polymorphism, which was originally present in a sample from a natural population in Switzerland, is distinct from a second cis-regulatory SNP previously identified in non-African D. melanogaster populations, implying that two independent cis-regulatory variants promoting high fiz expression segregate in non-African populations. Enzymatic analyses of Fiz protein expressed in E. coli demonstrate that it has ecdysone oxidase activity acting on both ecdysone and 20-hydroxyecdysone. Four of five fiz paralogs annotated to ecdysteroid metabolism also show reduced expression in Selected larvae, suggesting that malnutrition-driven selection favored general downregulation of ecdysone oxidases. Finally, as an independent test of the role of fiz in poor diet adaptation, we show that fiz knockdown by RNAi results in faster larval growth on the poor diet, but at the cost of greatly reduced survival. These results imply that downregulation of fiz in Selected populations was favored because of its role in suppressing growth in response to nutrient shortage. However, fiz downregulation is only adaptive in combination with other changes evolved by Selected populations, such as in nutrient acquisition and metabolism, which ensure that the organism can actually sustain the faster growth promoted by fiz downregulation.

evolutionary biology↗

bioRxiv2023

Experimental evolution of metabolism under nutrient restriction: enhanced amino acid catabolism and a key role of branched-chain amino acids

Periodic food shortage is a common ecological stressor for animals, likely to drive physiological and metabolic adaptations to alleviate its consequences, particularly for juveniles that have no option but to continue to grow and develop despite undernutrition. Here we study changes in metabolism associated with adaptation to nutrient shortage, evolved by replicate Drosophila melanogaster populations maintained on a nutrient-poor larval diet for over 240 generations. In a factorial metabolomics experiment we showed that both phenotypic plasticity and genetically-based adaptation to the poor diet involved wide-ranging changes in metabolite abundance; however, the plastic response did not predict the evolutionary change. Compared to non-adapted larvae exposed to the poor diet for the first time, the adapted larvae showed lower levels of multiple free amino acids in their tissues - and yet they grew faster. By quantifying accumulation of the nitrogen stable isotope 15N we show that adaptation to the poor diet led to an increased use of amino acids for energy generation. This apparent "waste" of scarce amino acids likely results from the trade-off between acquisition of dietary amino acids and carbohydrates observed in these populations. The three branched-chain amino acids (leucine, isoleucine and valine) showed a unique pattern of depletion in adapted larvae raised on the poor diet. A diet supplementation experiment demonstrated that these amino acids are limiting for growth on the poor diet, suggesting that their low levels resulted from their expeditious use for protein synthesis. These results demonstrate that selection driven by nutrient shortage not only promotes improved acquisition of limiting nutrients, but also has wide-ranging effects on how the nutrients are used. They also show that the abundance of free amino acids in the tissues does not, in general, reflect the nutritional condition and growth potential of an animal. Lay summaryJuvenile animals are particularly vulnerable to nutrient deprivation - they usually do not have an option of arresting their development and just trying to survive until food becomes plentiful; rather, they must attempt to grow and develop with whatever nutrients that can scrape. While they could obviously improve their lot by getting better at finding the scarce food, could they also adapt their physiology and metabolism in a way that would alleviate consequences of undernutrition? To find out we let populations of the fruit fly Drosophila melanogaster adapt during 240 generations to conditions of chronic larval nutrient shortage, and then studied their metabolism. We found that these populations evolved changes in their amino acid metabolism: their larvae are better at extracting amino acids from nutritionally poor diet and are able to grow faster (which requires a higher rate of protein synthesis), while maintaining lower levels of most amino acids in their system. This suggests improved cellular "logistics", with a higher turnover of raw materials associated with their lower stocks owing to their more efficient and immediate use. However, paradoxically, the malnutrition-adapted larvae also "waste" a substantial fraction of their amino acids by "burning" them for energy. They can afford this because of their improved extraction of scarce amino acid from the diet, but they may also be compelled to do this by a trade-off with absorption of dietary carbohydrates.

evolutionary biology↗

bioRxiv2022

Evolution under juvenile malnutrition impacts adult metabolism and fitness

Juvenile undernutrition has lasting effects on adult metabolism of the affected individuals, but it is unclear how adult physiology is shaped over evolutionary time by natural selection driven by juvenile undernutrition. We combined RNAseq, targeted metabolomics and genomics to study the consequences of evolution under juvenile undernutrition for metabolism of reproductively active adult females of Drosophila melanogaster. Compared to Control populations maintained on standard diet, Selected populations maintained for over 230 generations on a nutrient-poor larval diet evolved major changes in adult gene expression and metabolite abundance, in particular affecting amino-acid and purine metabolism. The evolved differences in adult gene expression and metabolite abundance between Selected and Control populations were positively correlated with the corresponding differences previously reported for Selected versus Control larvae. This implies that genetic variants affect both stages similarly. Even when well fed, the metabolic profile of Selected flies resembled that of flies subject to starvation. Finally, Selected flies had lower reproductive output than Controls even when both were raised under the conditions under which the Selected populations evolved. These results imply that evolutionary adaptation to juvenile undernutrition has large pleiotropic consequences for adult metabolism, and that they are costly rather than adaptive for adult fitness. Thus, juvenile and adult metabolism do not appear to evolve independently from each other even in a holometabolous species where the two life stages are separated by a complete metamorphosis.

evolutionary biology↗

bioRxiv2020

Pharmacologic inhibition of Protein Kinase C α and Protein Kinase C β halts renal function decline indirectly, by blunting hyperphagia, and directly reduces adiposity in the ZSF1 rat model of type 2 diabetes

Type 2 diabetes (T2D) and its complications can have debilitating, sometimes fatal consequences. Despite advances that address some of the metabolic aspects of T2D, for many patients these approaches do not sufficiently control the disease. As a result, an emerging therapeutic strategy is to target the pathobiological mechanisms downstream of T2D metabolic derangement that can result in organ damage, morbidity, and mortality in afflicted individuals. One such proposed mechanism involves the Protein Kinase C (PKC) family members PKC and PKC{beta}, which have been linked to diabetes-induced tissue damage to organs including the kidneys. To evaluate the therapeutic potential of dual inhibition of PKC and PKC{beta} in the context of T2D, we have evaluated a potent and orally bioavailable inhibitor, herein referred to as Cmpd 1, in the ZSF1 rat model of leptin-receptor deficiency, obesity-driven T2D. Therapeutic dosing of Cmpd 1 virtually halted renal function decline but did so indirectly by blunting the hyperphagia response of these animals. Beyond this clear but indirect effect, Cmpd 1 had direct and prominent effects on body weight and in liver and inguinal white adipose tissue (iWAT) when administered to ZSF1 obese rats.

pharmacology and toxicology↗

bioRxiv2018

Pathologically distinct fibroblast subsets drive inflammation and tissue damage in arthritis

The identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune mediated inflammatory diseases (IMIDs). However it remains unclear whether fibroblast subclasses with non-overlapping functions also exist and are responsible for the wide variety of tissue driven processes observed in IMIDs such as inflammation and damage. Here we identify and describe the biology of distinct subsets of fibroblasts responsible for mediating either inflammation or tissue damage in arthritis. We show that deletion of FAP+ synovial cells suppressed both inflammation and bone erosions in murine models of resolving and persistent arthritis. Single cell transcriptional analysis identified two distinct fibroblast subsets: FAP+ THY1+ immune effector fibroblasts located in the synovial sub-lining, and FAP+ THY1- destructive fibroblasts restricted to the synovial lining. When adoptively transferred into the joint, FAP + THY1- fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation whereas transfer of FAP + THY1+ fibroblasts resulted in a more severe and persistent inflammatory arthritis, with minimal effect on bone and cartilage. Our findings describing anatomically discrete, functionally distinct fibroblast subsets with non-overlapping functions have important implications for cell based therapies aimed at modulating inflammation and tissue damage.

immunology↗