[R01] Effect of weight loss on intermuscular adipose tissue (IMAT) signaling
Ente: National Institute of Diabetes and Digestive and Kidney Diseases
Scadenza: 2028-05-31
Importo max: 623.365 EUR
Paese: US
Descrizione
Intermuscular adipose tissue (IMAT) is marbled within skeletal muscle and appears to play a key role in the
obesity-induced risk of type 2 diabetes. What is not known is how IMAT promotes decreased muscle insulin
sensitivity. There is a critical need to understand how IMAT contributes to the risk of obesity-induced diabetes,
and how to intervene to minimize IMAT-induced muscle metabolic dysfunction. The overall objective for this
project is to determine the impact of weight loss on IMAT secretion of fibronectin and inflammatory cytokines
and eicosanoids. Our central hypothesis is that IMAT secretion of fibronectin promotes muscle insulin
resistance, and IMAT secretion of inflammatory cytokines and eicosanoids causes muscle inflammation, both
of which are diminished by weight loss. The rationale that underlies the proposed research is that clarifying the
extent to which weight loss alters the IMAT secretome will inform development of interventions to modify IMAT
and improve muscle insulin sensitivity in obese individuals. We propose two specific aims: Specific Aim 1.
Evaluate the impact of weight loss on IMAT secretion of fibronectin and the role of fibronectin in the IMAT
secretome to decrease insulin sensitivity in vitro. Preliminary data inform our working hypothesis that IMAT
secretes fibronectin that decreases muscle insulin sensitivity and is attenuated after weight loss in humans. In
vitro experiments will measure the extent to which IMAT fibronectin secretion explains IMAT-induced muscle
insulin resistance. We will study individuals with obesity before and after a 12-week weight loss intervention.
IMAT will be sampled using an ultrasound guided IMAT biopsy technique, insulin sensitivity measured using
insulin clamps, and IMAT content measured using MRI. Specific Aim 2 – Determine the influence of weight
loss on IMAT secretion of pro-inflammatory cytokines and eicosanoids and potency to cause inflammation and
decrease insulin sensitivity in vitro. We hypothesize, again based on preliminary data that the IMAT secretome
is less inflammatory after weight loss in obese individuals, with decreased potency to promote muscle
inflammation and insulin resistance. Muscle inflammatory response and insulin sensitivity with IMAT secretome
exposure will be compared before and after weight loss in vitro. The proposed research is innovative because
it represents a new and substantive departure from the status quo by testing specific IMAT secreted paracrine
signals rather than clinical associations with IMAT content. These contributions will be significant by identifying
the first IMAT paracrine signals that impact muscle and revealing the plasticity of IMAT through weight loss,
providing proof of concept that IMAT is a therapeutic target to combat muscle metabolic dysfunction.
Istituzione: UNIVERSITY OF COLORADO DENVER
PI: BRYAN C BERGMAN
Progetto: 5R01DK134706-04
Settori: National Institute of Diabetes and Digestive and Kidney Diseases
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