Brain-Gut Connection and Central Control of Metabolism Notes

Hypothalamus: Neuroendocrine Integration and Regulation

  • Brain and gut are intimately connected in regulating metabolism and controlling feeding behavior.
  • Hypothalamus plays a central role. Neuropeptides from the GI and endocrine systems bind to the hypothalamus. These signals align regulatory functions and the metabolic status of the body.
  • Sight/smell and consumption triggers neuronal/hormonal responses from the GI system impacting the brain. Gut neuropeptides are released which exert appetite- suppressing activity:
    • Insulin
    • Glucagon-like-peptide 1 (GLP-1)
    • Cholecystokinin (CCK)
    • Pancreatic polypeptide
    • Oxyntomodulin
    • Leptin (from adipose tissue)
    • Ghrelin (appetite-stimulating; released by stomach during fasting).
  • Stretching of the gastric wall inhibits ghrelin production.

Hypothalamic Nuclei

  • Arcuate nucleus: main relay station.
  • Ventromedial and dorsomedial nuclei: satiety centers. Lesions cause hyperphagia and obesity.
  • Lateral hypothalamic area: hunger center. Lesions cause hypophagia and starvation.
  • Arcuate nucleus responds to gut neuropeptides and changes in plasma levels of glucose, free fatty acids, and amino acids.
  • Arcuate nucleus sub-domains project to the paraventricular nucleus (orexigenic neurons), then to the nucleus tractus solitarius (NTS) and vagal efferent pathways.
  • Satiety signals from the liver and GIT travel through the vagus nerve and are integrated in the NTS.
  • Orexigenic vs anorexigenic peptides regulate feeding activity. Orexigenic peptides promote hunger and sustain the fasted state. Anorexigenic peptides promote satiety and increase metabolic rate.

CNS-Derived Brain-Gut Neuropeptides

  • First-order orexigenic peptides are secreted during fasting with ghrelin, inactivating receptors in the ventromedial nucleus, which obliterates satiety. Secretion follows circadian rhythm.
  • Neuropeptide Y (NPY) is the major product of first-order neurons promoting food-seeking behavior, regulating exocrine pancreatic function. NPY stimulates desire for food and suppresses leptin’s satiety-promoting function. Upregulated in crash diets.
  • Second-order orexigenic peptides (Orexins) from the paraventricular nucleus and ventrolateral hypothalamic nuclei have projections all over the brain especially in the prefrontal and limbic cortices. These dispersed connections establish the strong motivational and emotional influence of feeding behavior.
  • Hunger, via the orexins, can also trigger aggression. Orexins also stimulate wakefulness and suppress REM sleep.
  • Galanin is an orexigenic peptide, stimulating lactotroph proliferation (pronounced in hyperestrogenic state) and has strong connections to the hippocampus.
  • Anorexigenic neuropeptides from the CNS are released in response to food intake or increased nutrient levels, and secreted during catabolism (trauma, burns, infections).
  • Corticotropin-releasing hormone (CRH) is released by the hypothalamus, heightened in stressful situations.
  • POMC-derived melanocortins (α-MSH, β-MSH, γ-MSH and ACTH) mediate satiety by activating neurons in the ventromedial hypothalamic receptors.
  • Cocaine-and-Amphetamine-Regulated Transcript (CART) reduces cravings and increases motivation for other activities. Linked with dopaminergic and adrenergic systems, and pleasure/reward systems.
  • Galanin-like peptide (GALP) potentiates leptin's action, facilitating satiety and priming the body towards increased energy expenditure.
  • Exogenous corticosteroids downregulate CRH, promoting hunger.

Peripheral and Enteric Brain-Gut Neuropeptides

  • Actions are mediated by brain-gut neuropeptides arising from extracranial tissues; many from enteroendocrine cells in the GI tract.
  • Serotonin (from enterochromaffin cells): promotes adaptation to fasting:
    • Increased lipolysis
    • Decreased glucose uptake into adipose tissue
    • Increased hepatic glycogenolysis and gluconeogenesis
  • Ghrelin (from "A cells" of stomach's oxyntic glands): orexigenic; stimulates NPY release in the arcuate nucleus. Levels increase during fasting, hypoglycemia, and rising leptin levels.
  • Ghrelin levels are inversely proportional to insulin release. Inhibited by gastric distention.
  • Leptin (from adipose tissue): regulates body weight by limiting food intake and increasing energy expenditure. Activates anorexigenic neurons in the arcuate nucleus. Antagonist to ghrelin. Expression increased with inflammation and stress.
  • GLP-1 and GIP (incretins): stimulate insulin secretion. GIP (from K cells in duodenum/jejunum) inhibits gastric acid secretion and promotes pancreatic β-cell proliferation/survival. GLP-1 (from L-cells in distal small bowel/proximal colon) promotes glucose-dependent insulin secretion, reduces hepatic gluconeogenesis, and increases glucose uptake in skeletal muscle/adipose tissue; inhibits gastric acid secretion and gastric emptying. Centrally acts as anorexigenic peptide via the hypothalamus.
  • Oxyntomodulin (OXM): incretin-like peptide; anorexigenic and suppresses ghrelin.
  • Pancreatic Polypeptide (PP): regulates exocrine and endocrine pancreatic functions. Ingestion of food triggers release of PP. Induces anorexigenic response through the vagus nerve and the area postrema in the brainstem, in addition to its hypothalamic effects.
  • Cholecystokinin (CCK): secreted in response to fats and proteins. Induces contractions of the gallbladder. In the CNS, it acts on the arcuate, the ventromedial and the dorsolateral nuclei of the hypothalamus, producing appetite- suppressing signals.

Integrative Summary

  • Metabolism and energy balance is tightly regulated both centrally and peripherally.
  • Ghrelin promotes hunger while satiety is promoted by enteroendocrine peptides.
  • Body fat (via leptin) and physical activity (via sympathetic nervous system) influence central control of metabolism.
  • Metabolic state (fed/fasted) affects CNS activity through insulin.

Clinical Correlations

  • Reduced PP secretion leads to not feeling full after large meals.
  • Reduced basal circulating PP seen in Prader-Willi syndrome.
  • Increased PP release following food consumption leads to feeling satiety faster for Anorexia nervosa patients.
  • Hypothalamus influences other regions in the brain:
    • Prefrontal cortex – satiety improves cognitive activity
    • Amygdala – hunger evokes emotional responses and subsequent adaptive responses
    • Brainstem – hunger promotes wakefulness; satiety induces a relaxed state
  • Dysbiosis in inflammatory bowel diseases disrupts neuropeptide signaling.
  • Neurodegenerative diseases (Parkinson’s, Alzheimer’s) linked to pathologic changes in the gut.
  • Upregulated cortisol from increased activity of CRF and POMC leads to down-regulation of central neurotrophic factors.