Hypothalamic detection of macronutrients via multiple gut-brain pathways

Cell Metab. 2021 Mar 2;33(3):676-687.e5. doi: 10.1016/j.cmet.2020.12.018. Epub 2021 Jan 14.

Abstract

Food intake is tightly regulated by complex and coordinated gut-brain interactions. Nutrients rapidly modulate activity in key populations of hypothalamic neurons that regulate food intake, including hunger-sensitive agouti-related protein (AgRP)-expressing neurons. Because individual macronutrients engage specific receptors in the gut to communicate with the brain, we reasoned that macronutrients may utilize different pathways to reduce activity in AgRP neurons. Here, we revealed that AgRP neuron activity in hungry mice is inhibited by site-specific intestinal detection of different macronutrients. We showed that vagal gut-brain signaling is required for AgRP neuron inhibition by fat. In contrast, spinal gut-brain signaling relays the presence of intestinal glucose. Further, we identified glucose sensors in the intestine and hepatic portal vein that mediate glucose-dependent AgRP neuron inhibition. Therefore, distinct pathways are activated by individual macronutrients to inhibit AgRP neuron activity.

Keywords: AgRP; fat; food intake; glucose; gut-brain; hepatic portal vein; hypothalamus; intestine; spinal afferents; vagus nerve.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Agouti-Related Protein / metabolism
  • Animals
  • Brain / drug effects
  • Brain / physiology
  • Dietary Fats / metabolism
  • Dietary Fats / pharmacology
  • Glucose / metabolism
  • Glucose / pharmacology
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Intestines / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Neurons / metabolism*
  • Nutrients / metabolism*
  • Nutrients / pharmacology
  • Signal Transduction / drug effects
  • Sodium-Glucose Transporter 1 / metabolism
  • Vagus Nerve / drug effects
  • Vagus Nerve / physiology

Substances

  • Agouti-Related Protein
  • Dietary Fats
  • Sodium-Glucose Transporter 1
  • Glucose