tirsdag den 6. november 2018

NPY, AgRP, POMC and NUCB2 in ME

Hypothalamic Pro-opiomelanocortin (POMC) and Neuropeptide Y/Agouti-Related Peptide (NPY/AgRP) neurons are critical nodes of a circuit within the brain that sense key metabolic cues as well as regulate metabolism. Importantly, these neurons retain an innate ability to rapidly reorganize synaptic inputs and electrophysiological properties in response to metabolic state (1).

Exercise (single bout and/or chronic training) increases insulin sensitivity leading to improved insulin stimulated glucose uptake in muscle and reduced basal hepatic glucose production . Within the arcuate nucleus, the melanocortin system is an interface between signals of metabolic state and neural pathways governing energy balance and glucose metabolism. In particular, the orexigenic neuropeptide Y/Agoutirelated peptide (NPY/AgRP) neurons are activated in response to food deprivation, while the anorexigenic proopiomelanocortin (POMC)- expressing cells are inhibited . In addition to contributing to energy balance, the activity of arcuate NPY/AgRP and POMC neurons also have profound effects on glucose metabolism. These changes in cellular activity have been attributed to both native channel properties as well as (re)organization of synaptic connectivity (1 and references herein).

New research shows: Cellular and synaptic reorganization of arcuate NPY/AgRP and POMC neurons after exercise (1).

Nesfatin-1 is an 82–amino acid polypeptide derived from the precursor protein nucleobindin 2 (NUCB2), whose processing also yields nesfatin-2 and -3, two peptides with so far unknown functions (2).

Nesfatin-1 is involved in several processes including modulation of gastrointestinal functions, energy metabolism, glucose and lipid metabolism, thermogenesis, mediation of anxiety and depression, as well as cardiovascular and reproductive functions (2).

Use the link to se figure with NUCB2 and the hypothalamus (3): 

As you can se in the figure, the hypothalamus is a key brain area for maintaining glucose and energy homeostasis via the ability of hypothalamic neurons to sense, integrate, and respond to numerous metabolic signals.

Mitochondrial function has emerged as an important component in the regulation of hypothalamic neurons controlling glucose and energy homeostasis. Although the underlying mechanisms are not fully understood, emerging evidence indicates that mitochondrial dysfunction in hypothalamic neurons may contribute to the development of various metabolic diseases (4).

NPY, AgRP, POMC and NUCB2 in ME

NPY precursor, number of unique peptides identified in cerebrospinal fluid (table S1 in ref 5):
1) Controls: 4
2) ME patients: 7
3) Post  treatment  Lyme patients: 6

The plasma level of neuropeptide Y is elevated in ME patiens (6).

POMC, number of unique peptides identified in cerebrospinal fluid (table S1 in ref 5):
1) Controls: 1
2) ME patients: 2 
3) Post  treatment Lyme patients: 1

Some ME patients have single nucleotide plymorphism (SNP) in POMC (7).

The gene POMC (TSS1500, 5'UTR) is hypomethylated in peripheral blood mononuclear cells  (PBMC) from ME patients (8).

NUCB1 precursor, number of unique peptides identified in cerebrospinal fluid (table S1 in ref 5):
1) Controls: 29
2) ME patients: 43
3) Post  treatment Lyme patients: 51

NUCB2 precursor, number of unique peptides identified in cerebrospinal fluid (table S1 in ref 5):
1) Controls: 9
2) ME patients: 8
3) Post  treatment Lyme patients: 13

The gene NUCB2 (5'UTR) is hypomethylated in PBMC from ME patients (8).

The gene NUCB2 (5'UTR) is differentially methylated in PBMC from ME patient subtyes (9).


References

1) He et al: Cellular and synaptic reorganization of arcuate NPY/AgRP and POMC neurons after exercise. Mol Metab. 2018 Sep 12. pii: S2212-8778(18)30870-6. doi: 10.1016/j.molmet.2018.08.011 https://www.ncbi.nlm.nih.gov/pubmed/30292523

2) Schalla and Stengel: Current Understanding of the Role of Nesfatin-1. J Endocr Soc. 2018 Oct 1; 2(10): 1188–1206. Published online 2018 Sep 10. doi: [10.1210/js.2018-00246]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169466/

3) Figure from:  Diabetes. 2012 Aug; 61(8): 1920–1922.
and https://www.ncbi.nlm.nih.gov/pubmed/22826310

4) Jin and Diano: Mitochondrial Dynamics and Hypothalamic Regulation of Metabolism. Endocrinology, Volume 159, Issue 10, 1 October 2018, Pages 3596–3604,https://doi.org/10.1210/en.2018-00667 https://academic.oup.com/endo/article-abstract/159/10/3596/5091402?redirectedFrom=fulltext

5) Schutzer et al: Distinct Cerebrospinal Fluid Proteomes Differentiate Post- Treatment Lyme Disease from Chronic Fatigue Syndrome. PLOS One February 2011, volume 6, Issue  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017287

6) Fletcher et al: Plasma neuropeptide Y: a biomarker for symptom severity in chronic fatigue syndrome. Behav Brain Funct. 2010 Dec 29;6:76. doi: 10.1186/1744-9081-6-76 https://www.ncbi.nlm.nih.gov/pubmed/21190576

7) Smith et al: Polymorphisms in genes regulating the HPA axis associated with empirically delineated classes of unexplained chronic fatigue. PHARMACOGENOMICSVOL. 7, NO. 3COLLABORATIVE STUDY: CHRONIC FATIGUE SYNDROME – RESEARCH REPORT
https://www.futuremedicine.com/doi/10.2217/14622416.7.3.387

8) Trivedi et al: Identification of ME/CFS - associated DNA methylation patterns.
Plos One 2018, 13, 7 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201066

9) de Vega et al: Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics 2018, 10, 5 https://www.futuremedicine.com/doi/full/10.2217/epi-2017-015