Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production

Area of Science:

• Metabolic physiology
• Neuroendocrinology
• Gastrointestinal physiology

Background:

• Energy and glucose homeostasis depend on food intake and liver glucose production.
• The upper intestine plays a key role in nutrient absorption and influences food intake via an intestine-brain axis.
• A brain-liver axis has been proposed to regulate glucose production based on blood lipid levels.

Purpose of the Study:

• To investigate the hypothesis that upper intestinal lipids activate an intestine-brain-liver neural axis to regulate glucose homeostasis.
• To elucidate the neural pathways involved in lipid sensing in the upper intestine and their impact on glucose production.

Main Methods:

• Direct administration of lipids into the upper intestine of rodents.
• Pharmacological inhibition of acyl-CoA synthesis and neural pathways (tetracaine, MK-801).
• Surgical interventions including subdiaphragmatic vagotomy, gut vagal deafferentation, and hepatic vagotomy.

Main Results:

• Upper intestinal lipids increased long-chain fatty acyl-CoA (LCFA-CoA) levels and suppressed liver glucose production.
• Inhibition of LCFA-CoA synthesis or neural blockade abolished the lipid-induced suppression of glucose production.
• Vagotomy and central administration of MK-801 disrupted the intestine-brain-liver signaling, preventing glucose production inhibition.

Conclusions:

• Upper intestinal lipids activate a neural axis connecting the gut, brain, and liver to inhibit glucose production.
• This pathway, mediated by LCFA-CoAs and involving vagal nerve signaling, represents a novel mechanism for glucose homeostasis regulation.
• The findings reveal a previously unappreciated role of the upper intestine in sensing lipids to control hepatic glucose output.