ABSTRACT
Birth presents a metabolic challenge to cardiomyocytes as they reshape fuel preference from glucose to fatty acids for postnatal energy production1,2. This adaptation is triggered in part by post-partum environmental changes3, but the molecules orchestrating cardiomyocyte maturation remain unknown. Here we show that this transition is coordinated by maternally supplied γ-linolenic acid (GLA), an 18:3 omega-6 fatty acid enriched in the maternal milk. GLA binds and activates retinoid X receptors4 (RXRs), ligand-regulated transcription factors that are expressed in cardiomyocytes from embryonic stages. Multifaceted genome-wide analysis revealed that the lack of RXR in embryonic cardiomyocytes caused an aberrant chromatin landscape that prevented the induction of an RXR-dependent gene expression signature controlling mitochondrial fatty acid homeostasis. The ensuing defective metabolic transition featured blunted mitochondrial lipid-derived energy production and enhanced glucose consumption, leading to perinatal cardiac dysfunction and death. Finally, GLA supplementation induced RXR-dependent expression of the mitochondrial fatty acid homeostasis signature in cardiomyocytes, both in vitro and in vivo. Thus, our study identifies the GLA-RXR axis as a key transcriptional regulatory mechanism underlying the maternal control of perinatal cardiac metabolism.
Subject(s)
Fatty Acids , Glucose , Heart , Milk, Human , gamma-Linolenic Acid , Female , Humans , Infant, Newborn , Pregnancy , Chromatin/genetics , Fatty Acids/metabolism , gamma-Linolenic Acid/metabolism , gamma-Linolenic Acid/pharmacology , Gene Expression Regulation/drug effects , Glucose/metabolism , Heart/drug effects , Heart/embryology , Heart/growth & development , Homeostasis , In Vitro Techniques , Milk, Human/chemistry , Mitochondria/drug effects , Mitochondria/metabolism , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Retinoid X Receptors/metabolism , Transcription Factors/metabolismABSTRACT
BACKGROUND: Collaborations between health systems and community-based organizations (CBOs) are increasingly common mechanisms to address the unmet health-related social needs of high-risk populations. However, there is limited evidence on how to develop, manage, and sustain these partnerships, and implementation rarely incorporates perspectives of community social service organizations. To address these gaps, we elicited CBOs' perspectives on service delivery for clients, the impact of the Whole Person Care-Los Angeles (WPC-LA) initiative to integrate health and social care, and their suggestions for improving health system partnerships. METHODS: Using stakeholder engaged principles and a qualitative Rapid Assessment Process, we conducted brief surveys and in-depth semi-structured interviews with 65 key informants from 36 CBOs working with WPC-LA. RESULTS: Major themes identified by CBOs included: 1) the importance of a holistic, client-centered, continuously engaged approach that is reliant on regional partnerships; 2) benefits of WPC-LA expanding capacity and networks; 3) concerns about communication and redundancy hindering WPC-LA; and 4) a need for more equitable partnerships incorporating their approaches. CONCLUSIONS: CBOs value opportunities for integration with health systems, bring critical expertise to these partnerships, and seek to strengthen cross-sector collaborations. Early, equitable, and inclusive participation in the development and implementation of these partnerships may enhance their effectiveness, but requires policy that prioritizes and incentivizes sustainable and mutually beneficial partnerships.