# Metabolic Benefits of Leptin Reduction

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $644,008

## Abstract

Abstract
Metabolic Benefits of Leptin Reduction
Adipocytes have moved to center stage with respect to systemic metabolic control. They regulate metabolic
homeostasis for a variety of tissues. Adipocytes achieve this regulation on the basis of their unsurpassed
ability to store and neutralize excess lipids. Importantly, they interact with other critical organs through the use
of adipokines. Leptin and adiponectin are the two most prominent factors that have been widely studied. The
availability of floxed versions of both genes encoding these factors has offered us the opportunity to eliminate
both adipokines in the adult stage to varying degrees. Reducing leptin levels in adult obese animals has
yielded a number of surprising findings. We recently published these findings in Cell Metabolism, in which we
showed that a reduction in systemic leptin levels results in enhanced leptin and insulin sensitivity. In contrast,
elevating leptin levels in a transgenic manner, by as little as 50%, results in further leptin and insulin
resistance. Here, we aim to better define the mechanistic aspects of this phenomenon. This includes: a)
determining which anti-diabetic regimens rely on leptin-lowering effects to achieve their established actions; b)
elucidating the signaling mechanisms underlying leptin sensitization upon reducing the ligand concentrations;
c) gaining a firm understanding on the control of leptin production at the level of different fat-pads. Our
proposed experiments should provide significant new insights into leptin production and leptin action. We can
address these questions with a series of new and unique mouse models that we recently generated.
Specifically, we aim to: I) Determine the effects of acute and chronic leptin reduction on peripheral leptin and
insulin sensitivity. We will manipulate leptin receptor levels and downstream signaling mediators, obtain in vivo
signaling information for both leptin and insulin signaling in real time, address sexually dimorphic responses to
leptin reduction and investigate the impact of adiponectin on leptin expression. II) We will examine whether
anti-diabetic interventions rely on leptin lowering prior to weight loss. Here, we will focus on a number of
different established pharmacological agents for which we will “clamp” leptin levels transgenically at baseline
levels during treatment, or further reduce leptin levels with neutralizing anti-leptin antibodies to enhance the
effects of these agents. III) We will assess whether the improvements in central leptin action that we
established by lowering leptin levels, require central leptin receptor action to achieve improved read-outs. If so,
which subpopulation of neurons is critically involved in this process? IV) Determine the critical mediators that
govern leptin production and release, particularly in the visceral adipocyte. We will examine whether 3 and 2a
adrenergic receptors regulate leptin levels in the mature adipocyte. The Scherer/Elmquist te...

## Key facts

- **NIH application ID:** 10841625
- **Project number:** 5R01DK127274-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** JOEL K. ELMQUIST
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $644,008
- **Award type:** 5
- **Project period:** 2021-07-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841625

## Citation

> US National Institutes of Health, RePORTER application 10841625, Metabolic Benefits of Leptin Reduction (5R01DK127274-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10841625. Licensed CC0.

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