NIH grant: Defining the Role of Epidermal NADPH in Linking Skin Homeostasis to Systemic Metabolism. (1R01AR086828-01A1)

retained text

NIH grant 1R01AR086828-01A1: Defining the Role of Epidermal NADPH in Linking Skin Homeostasis to Systemic Metabolism.
Institute: {'code': 'AR', 'abbreviation': 'NIAMS', 'name': 'National Institute of Arthritis and Musculoskeletal and Skin Diseases', 'admin_org_id': '12500006', 'admin_funding_url': ''}. PI: Gerta N/A Hoxhaj. Award: $578211.
Start: 2026-08-07T00:00:00.
PROJECT SUMMARY: The skin is increasingly recognized as a metabolically active and endocrine organ, yet
the pathways that maintain its barrier function and influence whole-body metabolism remain poorly understood.
The epidermis must synthesize lipids and maintain antioxidant defenses to protect against reactive oxygen
species (ROS). Although oxidative stress has been linked to barrier disruption, how redox imbalance alters
epidermal lipid metabolism and whether such disruption influences systemic energy balance remain poorly
understood. Both lipid synthesis and antioxidant defense require NADPH, which is generated primarily by the
metabolic enzyme NAD kinase (NADK). However, because global NADK deletion is embryonically lethal, the
physiological roles of NADK and NADPH metabolism have remained unclear. Using an inducible, keratinocyte-
specific NADK knockout mouse model, we discovered that loss of NADK in the skin causes a profound redox
imbalance that produces a striking dual phenotype: impaired skin barrier integrity and systemic fat loss with
resistance to diet-induced obesity. These systemic effects occur independently of food intake or thermogenesis,
revealing a previously unrecognized skin-initiated metabolic signaling pathway. This proposal will test the
central hypothesis that epidermal NADPH depletion causes redox imbalance, which (1) disrupts local
epidermal lipid metabolism, leading to barrier failure, and (2) activates a redox-dependent skin-to-fat
signaling axis that drives systemic lipolysis. Aim 1 will determine how redox imbalance caused by epidermal
NADPH depletion leads to disruptions in lipid metabolism, including lipid peroxidation and suppressed de novo
lipogenesis, driving barrier failure. We will use isotope tracing, metabolomics, and lipidomics to define the specific
metabolic pathways disrupted. Furthermore, we will establish disease relevance by testing this axis in preclinical
models of atopic dermatitis (AD) and validating key signatures in human AD patient samples. Aim 2 will elucidate
the redox-dependent skin-to-fat signaling axis that drives systemic fat loss. Building on our finding that epidermal
redox stress induces skin-derived cytokines that promote lipolysis, we will use complementary genetic and
pharmacologic approaches to (1) define the upstream redox-sensitive regulation of cytokine induction in
keratinocytes, and (2) delineate the downstream signaling mechanisms through which these cytokines promote
adipose loss. By integrating in vivo genetics, in vitro keratinocyte cell culture, redox biochemistry, and advanced
metabolic profiling, this work will uncover fundamental principles of redox regulation in the skin and reveal how
epidermal metabolism influences systemic energy homeostasis. It will also establish the skin as an endocrine
organ that communicates metabolic stress to adipose tissue, advancing a new conceptual framework
for skin biology and systemic metabolism. These studies may identify epidermal redox metabolism as a
therapeutic target for treating both skin diseases and systemic metabolic disorders.

document fetched 2026-08-16 06:34