# Dissecting PKA activation of mTORC1 and its function in adipose tissue

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $515,775

## Abstract

Project Summary:
Obesity is at epidemic proportions in the US. Over 60% of the population is either overweight (Body Mass
Index [BMI] ≥25 to <30 kg/m2) or obese (BMI ≥30 kg/m2), placing them at risk for a large number of chronic
diseases, including insulin resistance, metabolic syndrome, and type 2 diabetes. The annual costs of obesity
exceed $100 billion, making it one of the most significant public health and economic issues facing the country.
Unfortunately, the treatment of obesity is unsatisfactory. Lifestyle and behavioral approaches have a modest,
and often transient, effect while FDA-approved therapeutic options targeting appetite or fat absorption have
poor tolerability and, in some cases, safety concerns. Thus, there is a critical need for novel approaches to
treat obesity. Agents acting via peripheral mechanisms to increase energy expenditure would be valuable. The
sympathetic nervous system (SNS) is well-known as an activator of brown adipose tissue (BAT) and the
“browning” of cells in white adipose tissue (WAT) depots to increase uncoupled mitochondrial respiration and
energy expenditure. Our earlier work established a signaling cascade from β-adrenergic receptors (βARs) 
cAMP  protein kinase A (PKA)  p38 MAP kinase (MAPK) to drive the transcription of brown adipocyte
genes such as uncoupling protein-1 (UCP1), PPAR-gamma coativator-1α (PGC-1α), and the broader program
of mitochondrial biogenesis.
We have discovered that the mTOR complex-1 (mTORC1) components mTOR and Raptor are phosphorylated
by PKA. This is a highly novel observation, since the `canonical' pathway to mTORC1 is through growth
factors and insulin. From in vivo studies in mice we find that blockade of mTORC1 with rapamycin, or genetic
deletion of Raptor specifically in adipose tissue, suppresses the ability of the βAR pathway in increase the
amount of UCP1-expressing `beige' adipocytes within white fat depots, and dampens UCP1 expression and
respiration in interscapular brown fat. The ability of laboratory animals and humans to expand these `beige'
adipocytes is closely correlated with resistance to weight gain and improved insulin sensitivity.
We have identified the phosphorylation sites on mTOR and Raptor and propose to test the physiological
consequences of cells and mice in which Ser791 of Raptor is changed to either Alanine (loss-of-function
mutation) or Aspartate (gain-of-function) by engineering a `knock-in' genetic construct. Since we now show that
there are two distinct routes to activation of mTORC1, we are also taking an unbiased proteomic approach to
identify the unique phosphorylation substrates of mTOR resulting from PKA activation vs insulin. Altogether,
these experiments will shed important mechanistic and physiological insight into the steps needed for `beige'
cell expansion, as well as the broader ability of the PKA mTORC1 pathway to function in other cell types.

## Key facts

- **NIH application ID:** 9983708
- **Project number:** 5R01DK116625-03
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** SHEILA COLLINS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $515,775
- **Award type:** 5
- **Project period:** 2018-08-22 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983708

## Citation

> US National Institutes of Health, RePORTER application 9983708, Dissecting PKA activation of mTORC1 and its function in adipose tissue (5R01DK116625-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9983708. Licensed CC0.

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