loading
loading
NIH grant 1R01DK146119-01A1: Establishing Memory in Adipose Tissue Influences Future Metabolic Outcomes in Obesity
Institute: {'code': 'DK', 'abbreviation': 'NIDDK', 'name': 'National Institute of Diabetes and Digestive and Kidney Diseases', 'admin_org_id': '12500020', 'admin_funding_url': ''}. PI: Rana K Gupta. Award: $790119.
Start: 2026-08-26T00:00:00.
PROJECT SUMMARY
Metabolic health varies widely among individuals with obesity, affecting risk for cardiometabolic disease
and response to weight-loss therapies. Understanding what drives differences in metabolic outcome and therapy
response in obesity is essential for advancing the development of precision medicine in obesity management.
Comparisons between “metabolically healthy” and “metabolically unhealthy” obesity (MHO vs. MUO) suggest
that how energy-storing white adipose tissue (WAT) remodels has it expands is a key determinant of insulin
sensitivity. Adaptive WAT remodeling supports metabolic health and involves angiogenesis, adipogenesis, and
maintenance of metabolically flexible adipocytes capable of regulated lipid handling and endocrine function. In
contrast, maladaptive WAT fibrosis and inflammation leads to adipocyte dysfunction and metabolic disease. The
mechanisms controlling these divergent remodeling outcomes and their influence on weight-loss therapy
response remain poorly defined.
Our preliminary data show that short-term pharmacological or physiological β-adrenergic stimulation
induces adaptive remodeling that leaves behind a persistent pool of metabolically flexible adipocytes, even after
the intervention ends. When challenged later with a high-fat diet, mice with these “trained” adipocytes still develop
obesity but are protected from maladaptive visceral WAT remodeling and insulin resistance. Remarkably,
epididymal adipocytes in this model exhibit a transcriptional profile similar to metabolically flexible visceral
adipocytes identified in human MHO, with enrichment of lipid metabolism pathways regulated by EBF
transcription factors.
We propose to leverage the legacy effects of these interventions as an experimental tool to understand
the determinants and consequences of healthy adipose remodeling in obesity. Our goals are to: 1) Define the
physiological benefits of adaptive visceral WAT remodeling, including effects on insulin sensitivity and
responsiveness to incretin-based therapies, and 2) Identify cellular and molecular determinants of adaptive vs.
maladaptive remodeling.
This model of adipose programming will yield generalizable insights into tissue “memory,” identify
biomarkers of adipose health, and inform strategies to enhance the durability and efficacy of obesity therapies.
More broadly, these studies provide a foundation for understanding how transient nutritional, pharmacological,
or environmental interventions can program long-term tissue function. Lessons learned in adipose tissue may
illuminate broader principles of tissue memory, metabolic resilience, and aging.document fetched 2026-09-06 02:47