Abstract Intermuscular adipose tissue (IMAT) exists between muscle fibers and under the muscle fascia, and is positively related to insulin resistance and sarcopenia. What is not known is how IMAT promotes decreased muscle size, strength, and insulin sensitivity. Thus, there is a critical need to address these gaps in knowledge because, until that need is met, the potential for IMAT as a target for interventions that prevent/treat type 2 diabetes and sarcopenia is unlikely to be realized. The overall objective for this project is to quantify the secretome of IMAT relative to visceral (VAT) and subcutaneous adipose tissue (SAT), and determine the relative potency of the IMAT secretome to cause inflammation, and decreased contractile protein expression and insulin sensitivity in vitro. Our central hypothesis is that the IMAT secretome promotes muscle inflammation, and decreases muscle mass, strength, and insulin sensitivity. The rationale that underlies this proposal is that clarifying how IMAT promotes decreased muscle size, strength, and insulin sensitivity will enable development of novel therapeutic interventions to prevent or treat sarcopenia and type 2 diabetes. To achieve our objective, we propose two specific aims: Specific Aim 1. Determine that IMAT and visceral adipose tissue have a secretome that is metabolically adverse when compared to subcutaneous adipose tissue in humans. Our preliminary data show that IMAT secretes inflammatory cytokines and eicosanoids similar to VAT. Our working hypothesis is that IMAT and VAT secrete inflammatory cytokines, adipokines, eicosanoids, and extracellular matrix proteins that promote metabolic dysfunction when compared to SAT. We propose to measure the secretome of IMAT, VAT and SAT in lean, obese, and obese individuals with pre-diabetes and type 2 diabetes. Muscle mass, strength, and insulin sensitivity will be measured using MRI, isokinetic dynamometry and hyperinsulinemic/ euglycemic clamps, respectively. Components of the IMAT secretome will be compared to SAT and VAT, and correlated to donor insulin sensitivity, strength, and muscle mass to reveal potential mechansims by which IMAT alters muscle function. Specific Aim 2. Establish the potency of the IMAT secretome to cause an inflammatory response, and decrease insulin sensitivity and contractile protein expression in vitro. Based on strong preliminary data, our working hypothesis is that IMAT and VAT secretome will increase the inflammatory response, and decrease insulin sensitivity and contractile protein expression relative to that from SAT. In vitro responses will be compared by group, and constituents of the IMAT secretome will be correlated to the change in cell culture outcomes to reveal potential mechanisms of action. The proposed research is innovative because it represents a substantive departure from the status quo by directly sampling IMAT in humans. This contribution will be significant because IMAT has never been collected from humans for detailed studies, and will reveal intermuscular adipose tissue as a new therapeutic target to combat sarcopenia and type 2 diabetes.

Narrative The proposed research is relevant to public health because identifying mechanisms by which intermuscular adipose tissue promotes insulin resistance and sarcopenia will likely provide new therapeutic targets to prevent and treat type 2 diabetes and muscle weakness and wasting, by identifying novel proteins acting as paracrine signals regulating tissue function. Additionally, this proposal may provide the rationale for altering intermuscular adipose tissue protein production, or skeletal muscle receptor sensitivity toward these signals. Thus, the proposed research is relevant to the NIH’s mission to enhance health, lengthen life and reduce illness and disability.