Mfge8 promotes obesity by mediating the uptake of dietary fats and serum fatty acids

Abstract

Fatty acids are integral mediators of energy storage, membrane formation and cell signaling. The pathways that orchestrate uptake of fatty acids remain incompletely understood. Expression of the integrin ligand Mfge8 is increased in human obesity and in mice on a high-fat diet, but its role in obesity is unknown. We show here that Mfge8 promotes the absorption of dietary triglycerides and the cellular uptake of fatty acid and that Mfge8-deficient (Mfge8−/−) mice are protected from diet-induced obesity, steatohepatitis and insulin resistance. Mechanistically, we found that Mfge8 coordinates fatty acid uptake through αvβ3 integrin– and αvβ5 integrin–dependent phosphorylation of Akt by phosphatidylinositide-3 kinase and mTOR complex 2, leading to translocation of Cd36 and Fatp1 from cytoplasmic vesicles to the cell surface. Collectively, our results imply a role for Mfge8 in regulating the absorption and storage of dietary fats, as well as in the development of obesity and its complications.

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

“…In vitro CRISPR knockout of ABCD1 gene in N9 microglia did not show upregulation of C1q or MFGE8 (data not shown), suggesting an indirect non‐cell‐autonomous process. Khalifeh‐Soltani et al reported MFGE8 upregulation by high‐fat treatment and demonstrated a role of MFGE8 in absorption of dietary triglycerides and the cellular uptake of fatty acids 37. In our study, increased VLCFA, in particular C26:0 LPC, triggered the expression of MFGE8, suggesting the altered metabolic milieu as one potential factor impacting MFGE8.…”

Mfge8 regulates enterocyte lipid storage by promoting enterocyte triglyceride hydrolase activity

“…We have previously reported that Mfge8 promotes enterocyte FFA uptake and that serum TG levels in Mfge8 -/-mice are significantly reduced after an olive oil gavage (9). FFAs released from dietary fat in the intestinal lumen are absorbed by enterocytes and trafficked to the endoplasmic reticulum (ER) where they are esterified into TG (11)(12)(13)(14).…”

“…In both mouse lines, enterocyte TG content was significantly increased after olive oil gavage despite a reduction in serum TG (Figure 1, A-C, the serum data for Mfge8 -/-mice was previously reported in ref. 9). The elevated TG content after olive oil gavage contrasts with our previously reported reduction in enterocyte TG content in Mfge8 -/-mice that have not had administration of an acute fat load (9).…”

“…9). The elevated TG content after olive oil gavage contrasts with our previously reported reduction in enterocyte TG content in Mfge8 -/-mice that have not had administration of an acute fat load (9). Mfge8 -/-and αvβ3/αvβ5 -/-mice also had increased stool TG levels at baseline and after olive oil gavage as compared with WT controls (Figure 1, D and E).…”

“…We have previously shown that the integrin ligand milk fat globule epidermal growth factor-like 8 (Mfge8) (7,8) regulates the absorption of dietary fat by enterocytes through binding of the αvβ3 and αvβ5 integrins (9). Integrin ligation by Mfge8 activates a PI3 kinase/mTORC2/PKCζ-dependent pathway that results in cellular uptake of FFAs.…”