# LIFR-alpha/JAK/STAT3-dependent Adipose Inflammation Contributes to Obesity-Associated NAFLD - Resubmissi

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $517,286

## Abstract

ABSTRACT 
Although adipose inflammation is associated with obesity, its role in reprogramming adipocytes and other cells 
in adipose towards the development of obesity’s metabolic comorbidities including steatosis remain unclear. The 
complex intracellular (stromal, vascular, immune, and adipocyte) interactions within adipose tissue ultimately 
regulate its size by balancing adipocyte triacylglyceride (TAG) lipolysis and synthesis. The inflammatory signaling 
of and between these cell types may also influence adipocyte responses to cAMP modulators. To understand 
the convergence of these interactions, we previously identified cytokine leukemia inhibitory factor (LIF) as a 
secretory molecule that increased adipose inflammation and lipolysis. Wild type mice on a high fat diet (HFD) 
demonstrated 7-fold higher LIF and IL-6 adipose mRNA than matched animals on normal diets. When 
recombinant LIF was administered to wild-type mice, it caused >50% loss of fat mass through JAK/STAT3-
dependent reprogramming of adipose tissue, increasing lipolysis and amplifying inflammation by altering the 
expression of other cyto/adipokines. JAK inhibitor treatment of rLIF-administered mice suppressed adipose loss 
through 1) inhibition of adipose inflammation as determined by decreased STAT3 phosphorylation, 2) decreased 
adipocyte lipolysis, and 3) inhibition of cyto/adipokine changes. To establish the importance of this signaling 
pathway to adipose inflammation, we selectively silenced LIF receptor (LIFR-α, gene LIFR) or STAT3 in 
adipocytes and assessed murine development in diet-induced obesity. Both models had decreased adipose 
inflammation resulting in a 50% increase in adipose mass and a ~75% reduction in total hepatic TAG levels 
compared to controls, limiting non-alcoholic fatty liver disease (NAFLD) and steatohepatitis in these mice. 
Conversely, with adipocyte silencing of the JAK/STAT counter-regulator SOCS3 in mice on HFDs, we observed 
the opposite phenotype with a ~30% reduction in adipose mass compared to controls. We hypothesize that a 
LIFR-α/JAK/STAT3-dependent Cytokine-Adipose-Hepatic Axis facilitates adipose inflammation, leading to 
increased lipolysis and altered expression of other cyto/adipokines. The activation of this axis limits adipose 
expansion, resulting in TAG mobilization from adipose to the liver and ultimately contributing to 
NAFLD/steatohepatitis. This inflammatory-driven axis also affects adipose responses to systemic metabolic 
change, sensitizing adipocytes to lipolytic regulation by other cAMP modulators. Finally, we present preliminary 
data that the IL-6 family of cytokines signal through JAK/STAT3 inducing the expression of adenylyl cyclase 5 
(ADCY5) to reprogram adipocytes in regulating lipid mobilization. SA1 will evaluate the contribution of the LIFR-α/JAK/STAT3 signaling cascade in adipocytes to the Cytokine-Adipose-Hepatic Axis. SA2 will use a genetics-based approach to verify that cytokine-mediated reprogramming ...

## Key facts

- **NIH application ID:** 10364225
- **Project number:** 1R01DK128166-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Rodney E Infante
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $517,286
- **Award type:** 1
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364225

## Citation

> US National Institutes of Health, RePORTER application 10364225, LIFR-alpha/JAK/STAT3-dependent Adipose Inflammation Contributes to Obesity-Associated NAFLD - Resubmissi (1R01DK128166-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10364225. Licensed CC0.

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