What does this research mean for the field?

Hepatocyte alpha-1b adrenergic receptors are required to mediate the sympathetic nervous system's stimulation of hepatic glucose production via glycogenolysis and gluconeogenesis during acute exercise. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to understand how the hepatic α1b adrenergic receptor affects blood sugar levels during exercise in mice.

June 7, 2026

2452-P: Hepatic Alpha 1b Adrenergic Receptor Controls Glycemia during Acute Exercise by Stimulation of Glycogenolysis and Gluconeogenesis

Key Points

This research aims to understand how the hepatic α1b adrenergic receptor affects blood sugar levels during exercise in mice.
Utilized liver-specific α1b-AR knockout (LA1BKO) mice for experiments.
Conducted treadmill exercise stress tests and norepinephrine tolerance tests.
Performed ex vivo liver perfusions with and without norepinephrine (NE) to assess metabolic function.
LA1BKO mice could not increase blood glucose during acute exercise when compared to control mice.
Norepinephrine injections increased blood glucose in control mice (exact values not provided), but had diminished effects in LA1BKO mice.
Ex vivo liver perfusions showed NE increased glucose release in control livers but not in LA1BKO, highlighting key differences in metabolic response.

Abstract

Introduction and Objective: Obesity and MASLD disrupt liver function but can be improved by lifestyle changes. The pathophysiology of MASLD and its treatments, such as exercise, are associated with changes in sympathetic nervous system (SNS) activity. The α1b adrenergic receptor (AR), which binds norepinephrine (NE) from sympathetic neurons and is abundant in mouse liver, may stimulate hepatic glucose production (HGP). Hepatocyte specific effects of adrenergic stimulation are challenging to study due to confounding endocrine effects and lack of hepatocyte specificity of pharmacological studies. We hypothesized that hepatic SNS signaling is required for the canonical glycemic response to acute exercise in mice. Methods: Liver-specific α1b-AR knockout (LA1BKO) mice were subjected to treadmill exercise stress test and norepinephrine (NE) tolerance test. Metabolic function was evaluated using ex vivo liver perfusions with and without NE. Results: LA1BKO mice maintained normal exercise capacity but could not upregulate blood glucose during acute exercise. Inability to increase blood glucose was related to the intensity of the bout. NE injections increased blood glucose in control mice but had a reduced effect in LA1BKO mice, suggesting contribution of lipolysis to induction of HGP. Ex vivo liver perfusions revealed that NE rapidly increased glucose release in control livers, but this response was absent in LA1BKO. Importantly, these effects were observed without changes in flow rate therefore were independent of vasoconstricting effects of adrenergic stimulation. Glycogen depletion occurred only in control livers after NE stimulation. While ketone production was unchanged, oxygen uptake rose with NE in controls, suggestive of increased mitochondrial activity necessitated by gluconeogenesis; this did not occur in LA1BKO mice, which also accumulated more lactate in blood. Conclusion: Hepatocyte α1b-AR mediates SNS regulation of hepatic glucose release during exercise and may influence metabolic disease. Disclosure S. Deja: None. F. Bégin: None. M.M. Fydryszewski: None. J. Rajendran: None. N. Pudelko-Malik: None. A. Caron: Speaker's Bureau; Ended; Novo Nordisk Canada Inc. J. Thyfault: None. J. Elmquist: Research Support; Current; Regeneron Pharmaceuticals Inc. S.C. Burgess: None. Funding National Institutes of Health (K01DK133630, R01DK100659)

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