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.
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.
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.
Komura et al. (2026) studied this question. Exendin-4 (Ex-4) was evaluated on Metabolic fuel selection (VO2, EE, RQ) and autonomic outputs (VNA, RSNA, LSNA). 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.