Berberine elevates cardiolipin in heart of offspring from mouse dams with high fat diet-induced gestational diabetes mellitus

Genevieve C. Sparagna,Bo Xiang,Marilyne Vandel,Grant M. Hatch,Laura K. Cole,Vernon W. Dolinsky

doi:10.1038/s41598-021-95353-4

Abstract

Berberine (BBR) is an isoquinoline alkaloid from plants known to improve cardiac mitochondrial function in gestational diabetes mellitus (GDM) offspring but the mechanism is poorly understood. We examined the role of the mitochondrial phospholipid cardiolipin (CL) in mediating this cardiac improvement. C57BL/6 female mice were fed either a Lean-inducing low-fat diet or a GDM-inducing high-fat diet for 6 weeks prior to breeding. Lean and GDM-exposed male offspring were randomly assigned a low-fat, high-fat, or high-fat diet containing BBR at weaning for 12 weeks. The content of CL was elevated in the heart of GDM offspring fed a high fat diet containing BBR. The increase in total cardiac CL was due to significant increases in the most abundant and functionally important CL species, tetralinoleoyl-CL and this correlated with an increase in the expression of the CL remodeling enzyme tafazzin. Additionally, BBR treatment increased expression of cardiac enzymes involved in fatty acid uptake and oxidation and electron transport chain subunits in high fat diet fed GDM offspring. Thus, dietary BBR protection from cardiac dysfunction in GDM exposed offspring involves improvement in mitochondrial function mediated through increased synthesis of CL.

Highlights

Berberine (BBR) is an isoquinoline alkaloid from plants known to improve cardiac mitochondrial function in gestational diabetes mellitus (GDM) offspring but the mechanism is poorly understood
We recently demonstrated that supplemental BBR in a high fat diet reduced adiposity and improved cardiac dysfunction in offspring of mouse dams with G DM12
Plasma levels of Non-esterified fatty acids (NEFA) were elevated in HF fed offspring from lean dams and this was reduced by treatment with BBR

Summary

Introduction

Berberine (BBR) is an isoquinoline alkaloid from plants known to improve cardiac mitochondrial function in gestational diabetes mellitus (GDM) offspring but the mechanism is poorly understood. BBR treatment increased expression of cardiac enzymes involved in fatty acid uptake and oxidation and electron transport chain subunits in high fat diet fed GDM offspring. Dietary BBR protection from cardiac dysfunction in GDM exposed offspring involves improvement in mitochondrial function mediated through increased synthesis of CL. BBR treatment of high fat fed offspring improved overall metabolic health and cardiac mitochondrial function; the mechanism for the cardioprotective effect was unknown. Since cardiolipin (CL) is a key mitochondrial membrane phospholipid known to regulate cardiac mitochondrial bioenergetics[13], we examined if changes in CL were, in part, responsible for the cardioprotective effects of BBR in the heart of high fat fed GDM offspring. Gene TBP TFIIB TAZ PTPMT PGS PGC1 SIRT1 CPT1 SREBP1 CD36 FABP1 FABP4 NDUFS3 SDHD COX5β ATP5i

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