Neuropeptides and Autophagy

Basics Of Neuropeptides And Autophagy


Two key players in healthy aging are proper neuropeptide signaling and healthy induction of autophagy. R

In this post, we will discuss how neuropeptides either induce or inhibit autophagy.


  1. Introduction To Neuropeptides And Autophagy
  2. Neuropeptides And Autophagy Quick Summary
  3. Agouti-Related Peptide and Proopiomelanocortin
  4. Intermedin
  5. Pituitary Adenylate Cyclase-Activating Polypeptide
  6. Gastrin-Releasing Peptide
  7. Angiotensin II
  8. Neuropeptide Y
  9. Ghrelin And Leptin
  10. Orexin
  11. Nesfatin-1
  12. Substance P
  13. Somatostatin
  14. Urocortin 1
  15. Brain Natriuretic Peptide

Introduction To Neuropeptides And Autophagy


Neuropeptides are small protein-like molecules (3–100 amino acid residues long) that act on neurons, helping their communication in the brain and body (ie signaling to release of neurotransmitters, growth factors, etc). R

They play many diverse roles in the central and peripheral nervous systems regulating the balance between excitation and inhibition (ie analgesia, reward, food intake, metabolism, reproduction, social behaviors, learning and memory. R R R

They are mainly present in neurons, glial cells, nonneural cells, and tissues/organs (endocrine and immune systems), their functions range from neuromodulators, neurohormones/hormones, and immune-modulators to growth factors. R R

There are over 100 different neuropeptides in the human body and in this post we are going to talk about the ones that play a paramount role in autophagy. R


Autophagy is the turnover of cells (by degradation and recycling of cellular components) and plays a very important role in development, inflammation, metabolism, and aging/longevity. R

This is paramount for the metabolic system (endocrine, cancer, starvation, infections) as well as central nervous system (such as preventing neurodegernation and enhancing neuroplasticity).

Autophagy decreases with age. R

There are 4 types of autophagy in the cell:

  • Macroautophagy – repair and recycle cell’s organelles and proteins consisting of initiation, nucleation, and expansion R
  • Microautophagy – recylcing cytoplasmic material R
  • Chaperone-mediated autophagy (CMA) – selective example (regulated by hsc70 complex) R
  • Mitophagy – degredation of mitochondria (regulated by NIX/BNIP3 and PINK1/parkin) R

Autophagy is executed by autophagy-related (Atg) genes, regulated by amino acid sensing and additional signals (such as growth factors, ROS, mTOR, AMPK, ULK1/2, Beclin, LC3, etc). R R

Neuropeptides And Autophagy Quick Summary

Activates Autophagy: R

  • Angiotensin II – produces ROS, cell senescence, heart enlargement
  • Ghrelin – restores insulin signaling, neuroprotective
  • Intermedin – attenuates myocardial infarction, improves cardiac survival/performance
  • Leptin – promotes tumor growth/invasion, decreases apoptosis
  • Neuropeptide Y – neuroprotective
  • Orexin – decreases cell viability
  • Somatostatin – decreases cell proliferation
  • Substance P – induces apoptosis, may play a role in hair cycles

Inhibits Autophagy: R

  • Ghrelin – reduces cell growth, apoptosis
  • PACAP – decreases apoptosis, neuroprotective, preserves mitochondrial activity
  • Urocortin 1 – decreases apoptosis 

Agouti-Related Peptide And Proopiomelanocortin

Agouti-Related Peptide (AgRP) and Proopiomelanocortin (POMC) are two orexigenic compounds that can control the body homeostasis, neuroendocrine outputs, and feeding behavior. R

When AgRP or POMC are released, they play a role on neurons of the arcuate nucleus of the hypothalamus which regulate feeding. R

For example, AgRP increase food intake, while POMC acts on suppressing feeding. R

In animal models, deletion of autophagy genes in POMC neurons increases feeding and weight gain, whereas deletion of autophagy genes in AgRP neurons reduces food intake (increases fasting) and weight gain. R R


Loss of autophagy genes in POMC neurons decreases α-melanocyte-stimulating hormone (alpha-MSH) levels, increases body weight, and raised adiposity/glucose intolerance, thus causing energy imbalance. R R

Low levels of glucose in the hypothalamus can induce autophagy (via activation of AMPK/mTOR) and is followed by lower POMC levels. R R

In animal models fed a high-fat diet, removal of AMPK expression (in the hypothalamus), can decrease autophagic activity, increase POMC expression, reduce of food intake/body weight. R

Exercise may help fix the energy imbalance caused by dysregulated autophagy genes on POMC/AgRP. R



Intermedin (aka adrenomedullin 2) is a POMC-derived neuropeptide (secreted by hypothalamus, pituitary, and other periphery tissues). R 

Intermedin can induce autophagy and may protect against heart failure (via increase in LC3-II, cAMP/PKA and ERK1/2-MAPK pathways). R R 

Pituitary Adenylate Cyclase-Activating Polypeptide

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the vasoactive intestinal peptide/secretin/glucagon family of peptides, which regulates neurotransmission, hormonal secretion, neuronal survival, neuroprotection, and neuroimmune responses. R R

PACAP is an antiapoptotic, anti-inflammatory, and vasodilating substance. R

For example, PACP can protect dopaminergic cells and mitochondria from apoptosis and autophagy in models of Parkinson’s Disease (PD). R

Gastrin-Releasing Peptide

Gastrin-releasing peptide (GRP) and its receptor are expressed in brain cancer cells. R

GRP may promote angiogenesis and tumorigenesis. R

Angiotensin II

Angiotensin II (Ang-II) acts as a hormone (increases blood pressure through vasoconstriction) and a neuropeptide in the central nervous system. R

In the vascular system, Ang-II can protect against vascular damage as it is able to remove damaged mitochondria and other cellular organelles and reactive oxygen species (ROS). R R

For example, in the heart it can protect against enlargement. R

In the kidneys, Ang-II can increase the expression of autophagic genes (ie LC3-II and beclin-1). R R

Neuropeptide Y 


Neuropeptide Y (NPY)  is an orexigenic neuropeptide that plays a role in many physiological functions such as food intake, energy homeostasis, circadian rhythm, cognition, stress response, immune regulation, neurogenesis, and neuroprotection. R R R R

NPY can act on 6 receptors (Y1-Y6) and when it acts on Y1 or Y5, it induces autophagy (via activation of PI3K, ERK1/2-MAPK, PKA and inhibition of mTOR). R R

Activating AMPK can increase autophagy (inhibit mTOR) and NPY expression. R

NPY expression decreases with age and caloric restriction (aka nutrient deprivation) can induce autophagy and NPY expression in the hypothalamus and cortical neurons, so may help with aging, metabolic syndroms, and neuroprotection. R R R R R

Ghrelin And Leptin

Ghrelin, the “hunger hormone”, is produced primarily in the stomach and secreted into the systemic circulation, and it regulation of food intake, gastrointestinal motility, and energy homeostasis. R

Leptin, the “satiety hormone”, is a peptide made by fat cells that helps to regulate energy balance. R

Ghrelin and leptin (for simplicity’s sake) oppose each others actions when expressed in the hypothalamus. R


In the liver, ghrelin can suppress fibrosis (via TGFb inhibition) and autophagy. R

In the heart, ghrelin can promote the survival of heart cells by decreasing autophagy (decreasing LC3-II, increasing mTOR/inhibiting AMPK, and increasing p38-MAPK). R

In skeletal muscles of diabetic mice, ghrelin can stimulate insulin secretion, restoring the suppressed mTOR-dependent autophagy. R

In human ovarian cancer cells, ghrelin can inhibit mTOR, enhance LC3-II levels, and induce apoptosis. R

NPY and ghrelin expression may help delay aging, as caloric restriction enhances growth hormone (GH) production and liver LC3-II levels in order to maintain normal glucose levels. R R


In liver and breast cancer cells, leptin can increase cancer growth. R 

By upregulating p53/FoxO3, leptin can induce autophagy, favoring tumor growth/invasion. R R

Since leptin is a major pathology of obesity and induces autophagy, it may be a connecting play between obesity and cancer. R


Orexins (aka hypocretin) are neuropeptides that regulate arousal, wakefulness, and appetite (secreted by hypothalamus. R

Orexin A can induce autophagy. R

Orexin A may be useful in colon cancer, as it increase of beclin-1. R


Nesfatin-1 (Nucleobindin-2) is a neuropeptide produced in the hypothalamus that regulates hunger and fat storage. R

Nesftatin-1 can inhibit orexigenic neurons and abnormal levels of nesfatin-1 has been seen in obesity, diabetes and cardiovascular diseases. R

Nesfatin-1 reduces autophagy (inhibits AMPK) and may make cancer worse. R

Substance P

Substance P (SP) belongs to tachykinins family and is expressed in neuronal cells, nonneuronal cells, and noninnervated tissues. R R

SP can activate skin levels of LC3-II and beclin-1, increasing autophagy. R R R

In the bladder, for example, theanine can decrease levels of SP and decrease the autophagy actions of SP. R 


Somatostatin or somatotropin release–inhibiting factor (SRIF) is a neuropeptide that is an endogenous inhibitor of GH from the hypothalamus. R R

SRIF is a neurotransmitter/neuromodulator has mainly inhibitory actions. R R R

SRIF has beneficial uses for cancer as it increases autophagy and decreases cell proliferation (decreases beclin-1 and increases LC3-II). R R R

Urocortin 1

Urocortin 1 is a neuropeptide secreted by the brain and vascular system that belongs to the corticotropin-releasing factor (CRF) family. R

High levels of urocortin 1 are upregulated in unhealthy hearts, as it reduces autophagy (inhibits beclin1) and has a cardioprotective role. R R

Brain Natriuretic Peptide

Brain natriuretic peptide (aka ventricular natriuretic peptide) is a neuropeptide that is also secreted by the brain and vascular system. R

It plays a role on regulating anxiety in HPA-axis dysregulation. R