Lipidomic Analysis of TRPC1 Ca2+-Permeable Channel-Knock Out Mouse Demonstrates a Vital Role in Placental Tissue Sphingolipid and Triacylglycerol Homeostasis Under Maternal High-Fat Diet.

Michael R Bukowski,James N Roemmich,Kate J Claycombe-Larson,Brij B Singh

doi:10.3389/fendo.2022.854269

Abstract

The transient receptor potential canonical channel 1 (TRPC1) is a ubiquitous Ca2+-permeable integral membrane protein present in most tissues, including adipose and placenta, and functionally regulates energetic homeostasis. We demonstrated that elimination of TRPC1 in a mouse model increased body adiposity and limited adipose accumulation under a high fat diet (HFD) even under conditions of exercise. Additionally, intracellular Ca2+ regulates membrane lipid content via the activation of the protein kinase C pathway, which may impact placental membrane lipid content and structure. Based upon this we investigated the effect of HFD and TRPC1 elimination on neutral lipids (triacylglycerol and cholesteryl ester), membrane lipids (phosphatidylcholine and phosphatidylethanolamine), and other multifunctional lipid species (unesterified cholesterol, sphingomyelins, ceramides). The concentration of unesterified cholesterol and sphingomyelin increased with gestational age (E12.5 to E 18.5.) indicating possible increases in plasma membrane fluidity. Diet-dependent increases ceramide concentration at E12.5 suggest a pro-inflammatory role for HFD in early gestation. TRPC1-dependent decreases in cholesterol ester concentration with concomitant increases in long-chain polyunsaturated fatty acid -containing triacylglycerols indicate a disruption of neutral lipid homeostasis that may be tied to Ca2+ regulation. These results align with changes in lipid content observed in studies of preeclamptic human placenta.

Highlights

High fat diet (HFD)-fed mothers and fathers are obese, hyperglycemic, and hyperlipidemic [1]
We have demonstrated that adipose proliferation is reduced in mice by knocking-out transient receptor potential canonical channel 1 (TRPC1) [11]
We have demonstrated that TRPC1 -/- animals have reduced adipocyte differentiation, reduced markers for autophagy, and increased expression of apoptosis markers, suggesting a change in neutral lipid storage and the sphingomyelin-ceramide pathway regulating nutrient transport, cell proliferation, and apoptosis [13, 14]

Summary

Introduction

High fat diet (HFD)-fed mothers and fathers are obese, hyperglycemic, and hyperlipidemic [1]. A parental HFD contributes to gestational programing of offspring obesity [2–5]. We have demonstrated that TRPC1 increases total body adiposity in mice by decreasing the efficacy of exercise to limit adipose accumulation under a HFD [6]. Placental lipid regulation is vital to the TRPC1KO Effects on Placental Lipids development of a healthy placenta and fetus. Obesity and a HFD are associated with increased risks of preeclampsia, gestational diabetes, placental inflammation, and fetal macrosomia [7–9]. Placentae from obese women contain 20% more esterified lipid than placental samples from non-obese women, which impairs placental function [10]. Investigating mechanistic relationships among adiposity, placental function, and putative placental tissue lipid contentassociated placental dysfunction are important for understanding how HFD-induced obesity may impact fetal development mediated via placental dysfunction

Objectives

Results

Conclusion