Fatty acid metabolism | EPFL Graph Search

Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes that generate energy and (2) anabolic processes where they serve as building blocks for other compounds. In catabolism, fatty acids are metabolized to produce energy, mainly in the form of adenosine triphosphate (ATP). When compared to other macronutrient classes (carbohydrates and protein), fatty acids yield the most ATP on an energy per gram basis, when they are completely oxidized to CO2 and water by beta oxidation and the citric acid cycle. Fatty acids (mainly in the form of triglycerides) are therefore the foremost storage form of fuel in most animals, and to a lesser extent in plants. In anabolism, intact fatty acids are important precursors to triglycerides, phospholipids, second messengers, hormones and ketone bodies. For example, p

The role and transcriptional regulation of FAM46A in adipocyte differentiation

Ann-Kristin Hov

Obesity is currently a leading global health concern. Treatments include undergoing a weight-loss regimen. However, successful weight-loss is variable, where the heritability of obesity is considered part of the cause. This patient variability to weight-loss was addressed by Carayol et al. (2017), where protein plasma level changes was associated to genetic variability and changes in BMI under a low-calorie diet intervention. A highly significant association region was found to regulate downstream gene FAM46A; coding for a nucleotidyl-transferase protein. Loss of function mutations in FAM46A have previously been discovered in multiple human diseases, such as osteogenesis imperfecta. However, there is a lack of understanding of FAM46Aâs function, especially in the context of adipose tissue and metabolism. This thesis aimed to follow up on the Carayol et al. study by investigating the transcriptional regulation of FAM46A and how the associated region is influencing this regulation, as well as how FAM46A is involved in adipose tissue function. When mapping the physical DNA interaction network around the associated region using chromosome conformation capture (3C) in human subcutaneous adipocytes (SGBS cells), no interactions between the FAM46A promoter and selected loci of the associated region were found. Interestingly, significant interaction peaks downstream of the promoter overlapped with regions of open chromatin and were enriched for transcription factor (TF) motifs that are involved in stem cell differentiation and TGFÎ² signalling. SMAD4, part of the TGFÎ² signalling pathway, binds to this region, indicating a potential regulator of FAM46A. To address FAM46Aâs potential role in adipocyte function, FAM46A expression was disrupted in vitro in differentiating adipocytes. Reduction of FAM46A expression in SGBS cells resulted in decreased expression of PPARG and CEBPA, the master regulators of adipogenesis, complemented by a reduction in lipid accumulation. Follow up studies in murine mesenchymal stem cells where Fam46a was over-expressed were controversial as this led to a decrease in adipogenic markers (Adipoq and PPARðŸ). Overall, disruption of FAM46A expression led to opposing changes in adipogenic potential, suggesting the requirement for a more stable cell system to study FAM46A in vitro. To further characterise the role of Fam46a, metabolic phenotyping of a Fam46a knockout (KO) mouse model under hyper-caloric stress was performed in collaboration with the IMG in Prague. This model revealed a significantly smaller mouse, and increased plasma alkaline phosphatase, as previously observed. When fed a high-fat diet, KO mice had reduced overall fat mass, improved glucose clearance and reduced adipocyte size in both subcutaneous and visceral white adipose tissue (subWAT/visWAT) depots. Transcriptomic analysis of these two depots revealed an up-regulation of genes expressed in ribosome related pathways in the subWAT, whereas the visWAT showed the up-regulation of fatty acid metabolism pathways, suggesting that the KO adipose tissue is more metabolically active. Other down-regulated pathways involved stem cell differentiation and BMP/TGFÎ²-signalling. In conclusion, this study found the possible regulation of the FAM46A promoter by TFs involved in adipogenesis regulation, such as SMAD proteins, as well as strengthening its possible functional involvement in TGFÎ² signalling by enrichment of this pathway in KO studies.

EPFL2021

Evidence for a neuromuscular circuit involving hypothalamic interleukin-6 in the control of skeletal muscle metabolism

Ludger Jan Elzuë Goeminne, Vera Monica Lemos Da Silva, Barbara Moreira Crisol, Eduardo Rochete Ropelle

Hypothalamic interleukin-6 (IL6) exerts a broad metabolic control. Here, we demonstrated that IL6 activates the ERK1/2 pathway in the ventromedial hypothalamus (VMH), stimulating AMPK/ACC signaling and fatty acid oxidation in mouse skeletal muscle. Bioinformatics analysis revealed that the hypothalamic IL6/ERK1/2 axis is closely associated with fatty acid oxidation– and mitochondrial-related genes in the skeletal muscle of isogenic BXD mouse strains and humans. We showed that the hypothalamic IL6/ERK1/2 pathway requires the α2-adrenergic pathway to modify fatty acid skeletal muscle metabolism. To address the physiological relevance of these findings, we demonstrated that this neuromuscular circuit is required to underpin AMPK/ACC signaling activation and fatty acid oxidation after exercise. Last, the selective down-regulation of IL6 receptor in VMH abolished the effects of exercise to sustain AMPK and ACC phosphorylation and fatty acid oxidation in the muscle after exercise. Together, these data demonstrated that the IL6/ERK axis in VMH controls fatty acid metabolism in the skeletal muscle.

2022

Deciphering the astrocyte-neuron metabolic cooperation in vivo

Manuel Raphael Zenger

Brain energy consumption is high and a very tightly regulated energy metabolism ensures correct performance. Neurons, the cells responsible for transmitting information via synapses, interact very closely with star shaped glial cells called astrocytes. Astrocytes play a pivotal role in the regulation of brain energy metabolism and for neurotransmission. Especially, in the case of glutamate, the main excitatory neurotransmitter in the brain, astrocytes are contributing to the clearing of otherwise potentially toxic levels of glutamate in the synaptic cleft. In addition, astrocytes are capable of providing neurons with lactate, which can be used as an additional source of energy in periods of increased demand, such as during neurotransmission. Lactate released by astrocytes is also a signal for neuronal plasticity. In this work, we addressed different aspects of the astrocyte-neuron metabolic coupling. Uncoupling proteins (UCPs) are proteins of the inner mitochondrial membrane that are capable of dissipating a proton gradient (uncoupling ATP production from respiration). Five different UCP isoforms have been described. UCP1 is essentially found in brown adipose tissue and is implicated in non-shivering thermogenesis, UCP2 is widely expressed and protecting against reactive oxygen species and UCP3 is mainly expressed in skeletal muscle tissue where a possible role in fatty acid metabolism has been described. UCP4 and 5 are essentially expressed in the brain, but their precise function still needs to be determined. In the present study, we showed that in neurons, UCP4 and UCP5 are predominantly expressed, as compared to the other UCPs. In astrocytes, UCP5 is the most abundant isoform, but also UCP2 and 4 are significantly expressed indicating an important role for these three UCPs in astrocytes. The role of UCP4 was further elucidated. For this purpose, a lentiviral overexpressing UCP4 construct was produced and characterized. This construct overexpressing UCP4 at the mitochondria allowed to demonstrate a neuro-protective role of UCP4 expression in astrocytes. In a complementary approach to study neuron-astrocyte metabolic coupling, the role of different astrocytic and neuronal genes in memory and learning was explored in a spatial learning paradigm. Mice were trained 1 to 9 days in a radial maze. The gene analysis showed that genes involved in lactate production and utilization such as lactate dehydrogenases were highly increased. A gene involved in the shuttling of lactate from astrocytes to neurons, such as monocarboxylate transporter 1 was also upregulated. An unexpected decrease in glucose transporter 1 and decrease in hexokinase 2 expression were observed. Finally, genes involved in glycogen metabolism were upregulated. Na+/K+-ATPase alpha2 isoform (ATP1A2), which plays a key role in re-establishing Na+ homeostasis disrupted by the co-transport of Na+ along with glutamate during glutamate uptake, was upregulated following spatial learning. Using a lentiviral transgenesis method, an attempt was made to downregulate the expression of the ATP1A2 in vivo. However, this technique did not allow us to produce sufficient knock down to study the role of ATP1A2 in vivo. Preliminary data for an alternative method are shown. Overall, the set of results presented here provides additional support for the existence of a dynamically regulated neuron-astrocyte metabolic coupling.

EPFL2015