Changes in lipid metabolism in the liver during adaptive thermogenesis

Author(s)

Victor Azevêdo Vieira

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2023-11-23

Examining board members

Luiz Osório Silveira Leiria; Luiz Carlos Carvalho Navegantes; Lício Augusto Velloso

• Advisor: Luiz Osório Silveira Leiria

Abstract

The crosstalk between adipose tissue (AT) and liver is essential for maintaining metabolic homeostasis in different conditions of energy demand. The flow of fatty acids (FAs) that are secreted by the AT through lipolysis migrate to the liver, where they then impact lipid and glucose metabolism. In situations of negative energy balance, such as exposure to cold, this flow is increased under adrenergic stimulation but does not result in hepatic steatosis, in addition to being necessary for thermogenic activity performed in brown adipose tissue (BAT). Based on this evidence, and on the fact that the liver exports triglycerides (TGs) conveyed in VLDL to the BAT during cold weather, we wonder what alterations in hepatic lipid metabolism occur in the face of cold heat stress and which, in turn, influence the lipidoma make VLDL. To this end, we hypothesize that the process of adaptive thermogenesis induces metabolic and lipid profile changes in the liver that allow it not to accumulate fat and export VLDL to sustain the thermogenic activity of BAT. Therefore, we evaluated the changes in lipid metabolism that occur in the liver during adaptive thermogenesis. Mice were equally divided into 4 groups: Control (zero time): Animals under thermoneutral condition (30 ºC); Groups of 1, 3 and 7 days of acclimatization to the cold (5 ºC). Our results prove that acclimatization to cold led to the reduction of genes involved in new liver lipogenesis, mainly Scd1. We observed an increase in the presence of polyunsaturated fats (PUFAs), especially those of omega-3, in the liver, only in a chronic form of cold challenge, at the same time that we saw the normalization of TGs levels, which under acute stimulus, restrictions increased. Lipidomics of the livers of these animals revealed profound changes in the profile of FAs that incorporate TGs. In thermoneutrality, there is a predominance of monounsaturated fats (MUFAs) and saturated fats (SFAs), while, after 7 days of acclimatization to the cold, PUFAs such as DHA, EPA and ARA are predominantly incorporated into TG instead of MUFAs and SFAs. The gene and protein expression of the rate-limiting enzyme for the biosynthesis of the above-mentioned PUFAs, Fads2, was increased in front of the cold in the white AT, while there was no alteration in the liver and in the BAT. Evaluating the oxygen consumption of the liver, we observed the increase in the phosphorylative presentation (OXPHOS), but we noticed the decay of beta-oxidation in the times of acclimatization to the cold. This data was corroborated by the increase in coenzyme Q (CoQ) and acylcarnitine accumulation. In the final step, we evaluated the lipid profile of VLDL extraction. Once again, we noticed changes regarding the incorporation profile of FAs to TGs. PUFAs are incorporated into the TG in greater uses in face of the cold challenge already under acute stimulus and remain during longer acclimatization time. The data in general suggest that the liver, during adaptive thermogenesis, shapes its lipid metabolism in order to spare specific species of FAs that were captured with the increase in lipolysis and Fads2 activity in WAT. The profile of these FAs is modified for incorporation into new TGs that will be exported in the form of VLDL, and that will sustain the thermogenic activity of BAT. (AU)

• FAPESP's process: 21/01311-6 - 12-Lipoxygenase as a rate-limiting step to promote brown fat/liver cross talk and suppress hepatosteatosis in high-fat diet fed mice
• Grantee: Víctor Azevêdo Vieira
• Support Opportunities: Scholarships in Brazil - Master