# Control of Energy Balance by ApoJ Signaling

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $437,500

## Abstract

Hypothalamic feeding circuits are essential for the maintenance of energy balance. Impairments in this feeding
regulatory system cause hyperphagia, which then promotes adiposity and weight gain. However, knowledge of
the critical anorexigenic signaling cascade involved in the hypothalamus remains incomplete. ApolipoproteinJ
(ApoJ) was not previously suspected to be involved in hypothalamic control of feeding behavior and energy
balance. We now have provided the preliminary data that ApoJ functions as such an anorexigenic molecule,
targeting leptin signaling and energy balance in the hypothalamus, which could be mediated via the LRP1 (low-
density lipoprotein receptor-related protein-1) signaling cascade. We found that centrally administered ApoJ in
mice lead to anorexia and weight loss, whereas deletion of hypothalamic ApoJ results in hyperphagia and
sever obesity. Specifically, deficiency of ApoJ in astrocytes, but not in AgRP, POMC, and SF-1 neurons, leads
to obesity, suggesting that astrocytic ApoJ is important in regulating normal body-weight homeostasis. Like
leptin, ApoJ activated Stat3 in leptin receptor (LepR)-expressing neurons but this effect was abolished in LepR-
deficient db/db mice, indicating the necessity of LepR signaling for ApoJ's effect. Importantly, ApoJ or leptin-
induced food intake was significantly impaired in mice lacking LRP1 in AgRP neurons. Moreover, we found that
genetic variant in ApoJ and LRP1 gene is associated with human obesity, suggesting the important link
between human disease and ApoJ/LRP1. We thus hypothesize that the ApoJ → LRP1 axis, coupled with the
LepR system, is a novel anorexigenic signaling pathway that is central for the maintenance of normal body-
weight homeostasis and energy balance. In this grant, Aim1 will establish the functional importance of ApoJ in
astrocytes in the control of energy balance. Aim2 will determine the biological function of LRP1 in regulating
energy balance. Aim 3 will elucidate the cellular mechanism(s) underlying the effect of ApoJ on leptin signaling.
To accomplish these aims, we will use state-of-the-art technologies, including a conditional floxed ApoJ and
LRP1 model to clarify the specific role of ApoJ/LRP1 action and neuron-specific gene manipulation to test
cellular mechanisms of ApoJ's anorexigenic action in an in vivo context. These studies provide a unique
opportunity to establish a new paradigm in which ApoJ and LRP1 are key determinants of energy balance, and
may offer a novel target for the treatment of obesity and diabetes.

## Key facts

- **NIH application ID:** 10197311
- **Project number:** 3R01DK106076-04S1
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** YOUNG-BUM KIM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $437,500
- **Award type:** 3
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197311

## Citation

> US National Institutes of Health, RePORTER application 10197311, Control of Energy Balance by ApoJ Signaling (3R01DK106076-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10197311. Licensed CC0.

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