What is the clinical evidence from this study?

Study design: Other. Intervention: Exendin-4 (Ex-4). Primary outcome: Metabolic fuel selection (VO2, EE, RQ) and autonomic outputs (VNA, RSNA, LSNA).

What question did this study set out to answer?

This study investigates how Exendin-4 alters metabolic fuel use and autonomic outputs in rats.

May 14, 2026

Lumbar, But Not Renal or Vagal, Sympathetic Nerve Activation During GLP-1 Agonist–Induced Hyperglycemia with Fat-Dominant Metabolism

Key Result

Exendin-4 administration in rats induced a biphasic shift to fat-dominant metabolism and increased blood glucose, accompanied by suppressed renal but increased lumbar sympathetic nerve activity.

Key Points

This study investigates how Exendin-4 alters metabolic fuel use and autonomic outputs in rats.
Male Wistar rats were implanted with electrodes for nerve activity and glucose monitoring.
Ex-4 was administered via three routes, and oxygen consumption and energy expenditure were continuously recorded.
Changes in metabolic substrate utilization were analyzed post-administration.
Ex-4 induced a biphasic shift from carbohydrate to fat metabolism, with an RQ decline to ~0.75.
Blood glucose increased during the fat-dominant phase, reflecting enhanced hepatic glucose output.
There was a ~60% reduction in renal sympathetic nerve activity and an increase in lumbar sympathetic nerve activity 15–40 min post-Ex-4.

Structured PICO

Population

Male Wistar rats chronically implanted with electrodes for cervical vagal nerve activity (VNA), renal sympathetic nerve activity (RSNA), lumbar sympathetic nerve activity (LSNA), arterial pressure, ECG, and interstitial glucose monitoring, along with intraperitoneal, portal, and intravenous catheters

Intervention

Exendin-4 10 µg/kg administered via intraperitoneal, portal, or intravenous route

Outcome

Alterations in metabolic fuel selection (oxygen consumption, energy expenditure, respiratory quotient) and autonomic outputs (VNA, RSNA, LSNA)surrogate

In a rat model, Exendin-4 induces a shift to fat-dominant metabolism and alters autonomic nerve activity, suggesting a sympathetic mechanism compensating for shifting substrate availability.

Abstract

Exendin-4 (Ex-4), a long-acting GLP-1 receptor agonist and the native peptide on which the antidiabetic drug exenatide is based, is known to acutely influence energy metabolism and autonomic function. However, the real-time relationship between substrate utilization and coordinated sympathetic–vagal activity has not been fully elucidated. This study aimed to determine how Ex-4 alters metabolic fuel selection and autonomic outputs in freely moving rats. Male Wistar rats were chronically implanted with electrodes for cervical vagal nerve activity (VNA), renal sympathetic nerve activity (RSNA), lumbar sympathetic nerve activity (LSNA), arterial pressure, ECG, and interstitial glucose monitoring, along with intraperitoneal, portal, and intravenous catheters. After recovery, Ex-4 (10 µg/kg) was administered via one of three routes, and oxygen consumption (VO 2 ), energy expenditure (EE), and respiratory quotient (RQ) were continuously recorded. VO 2 and EE remained largely unchanged. In contrast, RQ exhibited a biphasic response—an initial rise followed by a decline to ~0.75. Substrate analysis showed an early increase and subsequent decline in carbohydrate utilization, accompanied by a delayed increase in lipid utilization, indicating a shift from carbohydrate- to fat-dominant metabolism. Blood glucose increased during the fat-utilizing phase. Autonomic recordings revealed route-independent suppression of RSNA (~60%) immediately after Ex-4, whereas LSNA increased 15–40 min after administration. VNA increased promptly across all routes, with sustained elevation after intraperitoneal and intravenous injection. These findings demonstrate that Ex-4 induces a characteristic biphasic shift in metabolic fuel use without altering total energy expenditure. The increase in blood glucose during the fat-dominant phase may reflect enhanced hepatic glucose output driven by increased sympathetic nerve activity, highlighting a sympathetic mechanism that compensates for shifting substrate availability. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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