Altered hepatic glucose homeostasis in AnxA6-KO mice fed a high-fat diet

Abstract

Annexin A6 (AnxA6) controls cholesterol and membrane transport in endo- and exocytosis, and modulates triglyceride accumulation and storage. In addition, AnxA6 acts as a scaffolding protein for negative regulators of growth factor receptors and their effector pathways in many different cell types. Here we investigated the role of AnxA6 in the regulation of whole body lipid metabolism and insulin-regulated glucose homeostasis. Therefore, wildtype (WT) and AnxA6-knockout (KO) mice were fed a high-fat diet (HFD) for 17 weeks. During the course of HFD feeding, AnxA6-KO mice gained less weight compared to controls, which correlated with reduced adiposity. Systemic triglyceride and cholesterol levels of HFD-fed control and AnxA6-KO mice were comparable, with slightly elevated high density lipoprotein (HDL) and reduced triglyceride-rich lipoprotein (TRL) levels in AnxA6-KO mice. AnxA6-KO mice displayed a trend towards improved insulin sensitivity in oral glucose and insulin tolerance tests (OGTT, ITT), which correlated with increased insulin-inducible phosphorylation of protein kinase B (Akt) and ribosomal protein S6 kinase (S6) in liver extracts. However, HFD-fed AnxA6-KO mice failed to downregulate hepatic gluconeogenesis, despite similar insulin levels and insulin signaling activity, as well as expression profiles of insulin-sensitive transcription factors to controls. In addition, increased glycogen storage in livers of HFD- and chow-fed AnxA6-KO animals was observed. Together with an inability to reduce glucose production upon insulin exposure in AnxA6-depleted HuH7 hepatocytes, this implicates AnxA6 contributing to the fine-tuning of hepatic glucose metabolism with potential consequences for the systemic control of glucose in health and disease.

Annexins in Adipose Tissue: Novel Players in Obesity

“…Systemic lipid levels of AnxA6-deficient animals were also comparable to controls after a high fat diet for 17 weeks [61,62]. Most interestingly, AnxA6 KO-mice gained less adipose tissue during high fat feeding [61,62], which might be in line with the impaired proliferation observed in AnxA6-depleted preadipocytes [68]. On the other hand, and in contrast to the cell-based studies described above [68], circulating leptin and adiponectin levels were slightly reduced in high fat diet fed AnxA6 KO-mice [61,62].…”

“…The plasma membrane and endocytic compartments represent the most common AnxA6 localizations [26,30,63,66,115,116,117,118], but AnxA6 is also found along the secretory pathway [23,25,119], mitochondria [120] and lipid droplets [61,121]. Like other annexins, and depending on the cellular localization and repertoire of interaction partners, AnxA6 participates in many cellular activities, some of which potentially relevant for adipose tissue function, such as endo- and exocytosis, signal transduction, cholesterol homeostasis, stress response [23,25,26,27,30,64,94,116] and lately, neutral lipid accumulation [61,62].…”

“…Despite increased lipid storage in AnxA6-depeleted 3T3-L1 adipocytes, circulating triglycerides, free fatty acids and cholesterol were normal in AnxA6 KO-mice [68]. Systemic lipid levels of AnxA6-deficient animals were also comparable to controls after a high fat diet for 17 weeks [61,62]. Most interestingly, AnxA6 KO-mice gained less adipose tissue during high fat feeding [61,62], which might be in line with the impaired proliferation observed in AnxA6-depleted preadipocytes [68].…”

“…Most interestingly, AnxA6 KO-mice gained less adipose tissue during high fat feeding [61,62], which might be in line with the impaired proliferation observed in AnxA6-depleted preadipocytes [68]. On the other hand, and in contrast to the cell-based studies described above [68], circulating leptin and adiponectin levels were slightly reduced in high fat diet fed AnxA6 KO-mice [61,62]. Lower fat mass is usually associated with higher adiponectin and improved glucose homeostasis [21].…”

Annexin A6 as a cholesterol and nucleotide binding protein involved in membrane repair and in controlling membrane transport during endo- and exocytosis

“…Further studies has revealed, that the number of observations suggesting functioning of AnxA6 in exocytosis is limited. Investigators, however, agree that this multifunctional protein plays a regulatory role in membrane trafficking during exocytosis too Cairns et al 2018].…”