# Adipocyte lipolysis of oxidized neutral lipids regulates insulin signaling during acute stress.

> **NIH NIH F31** · UNIVERSITY OF VIRGINIA · 2020 · $19,253

## Abstract

PROJECT SUMMARY/ABSTRACT
 Acute hyperglycemia and systemic insulin resistance (IR) often develop after injury or surgery. This stress
response, appropriately known as critical illness diabetes, leads to increased post-operative complications and
mortality. Insulin administration reduces hyperglycemia in some patients, but has a risk of hypoglycemia. The
underlying mechanism of post-operative IR is largely unknown, which limits alternative therapies and
emphasizes the need to elucidate the pathophysiology. It is, however, known that surgical animal models rapidly
develop adipose IR. Impaired insulin action in adipose alone can result in whole body IR and hyperglycemia.
Therefore, this proposal will focus on how adipocyte lipolysis contributes to stress-induced IR.
 Inhibition of mTOR complexes 1 and 2, kinase complexes integral to insulin signaling, is associated with
the onset of IR. Our previous work demonstrates that catecholamine-induced attenuation of insulin signaling
requires lipolysis of the neutral lipids triacylglycerols (TAGs) and causes mTOR complex dissociation. We
recently observed that the presence of lipolytic products of oxidized neutral lipids (oxNL) induces mTOR complex
dissociation. We hypothesize that lipolysis breaks down oxidized TAGs into oxidized fatty acids (oxFAs),
which cause mTOR complex dissociation and attenuation of insulin signaling within adipocytes during
stress response.
 To this purpose, we propose the following aims. In Aim 1, we will define the oxFAs responsible by
examining in vitro whether oxidation of known polyunsaturated FAs generates products that cause mTOR
complex dissociation. Additionally, we will elucidate the type responsible by class-specific chemical derivitization
of oxFAs. In Aim 2, we will determine the role of adipose lipolysis and oxFA-mediated mTOR complex inhibition
during the acute stress response by treating wild-type and adipose-specific adipose triglyceride lipase null mice
with β receptor agonists. We will also stimulate the onset of the stress response by subjecting mice to a
hypovolemic model of acute trauma. The potential effect of oxFA production on mTOR complex dissociation and
the development of IR within adipose will be determined. Our work will elucidate a novel role for oxNLs and their
lipolytic products in the regulation of insulin signaling. Defining the mechanism by which catecholamine-
stimulated lipolysis attenuates insulin signaling will provide novel therapeutic targets for improved post-operative
glucose homeostasis.
 The research project proposed will be carried out in conjunction with a rigorous training plan composed
of the following: integrative coursework and interactive training, participation in research meetings and seminars,
participation in scientific conferences, and professional development. The combination of the proposed research
along with an active training plan will yield meaningful contributions to the field and the training required to excel
as a s...

## Key facts

- **NIH application ID:** 9911180
- **Project number:** 1F31DK121482-01A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Katelyn Wellcome Ahern
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $19,253
- **Award type:** 1
- **Project period:** 2020-07-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9911180

## Citation

> US National Institutes of Health, RePORTER application 9911180, Adipocyte lipolysis of oxidized neutral lipids regulates insulin signaling during acute stress. (1F31DK121482-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9911180. Licensed CC0.

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