The Role of Hypothalamic Neuropeptides in Regulation of Liver Functions in Health and Disease
and Sharon DeMorrow 1,2,*Round 1
Reviewer 1 Report
The manuscript is an interesting review on the role and effects od endogenous neuropeptides on liver function and regulation.
CRH paragraph - the authors should link CRH effects with those of POMC cited in the previous paragraph. CRH stimulates POMC release and cleavage so that to have MSH and ACTH. This should be mentioned
Author Response
CRH paragraph - the authors should link CRH effects with those of POMC cited in the previous paragraph. CRH stimulates POMC release and cleavage so that to have MSH and ACTH. This should be mentioned
Thank you for this suggestion. We added the following paragraph (lines 429-435)”
Stress-induced CRH stimulates the anterior pituitary gland to produce POMC, the precursor of ACTH, a-MSH and other neuropeptides with role in regulation of feeding behavior and energy balance [119,120]. The CRH/ACTH mediated neuroendocrine signaling to the adrenal glands, also known as the hypothalamic-pituitary-adrenal (HPA) axis, is a stress response pathway, resulting in increased systemic levels of glucocorticoids that act on vital organs including the liver, to maintain continuous energy balance as well as metabolic and immunological homeostasis [4].
Reviewer 2 Report
Overall, this is a well written and comprehensive review publication and offers a good overview on the role of different neuropeptides in liver normal and pathological functioning. However, some points need to be clarified.
My comments:
Line 84 - From histological point of view there are only four kinds of tissues: epithelial, connective, muscular and nervous. Therefore, such terms as “gastrointestinal tissue”, “placenta tissue, “liver tissue” or “neoplastic tissue” are not justified. The authors terribly confuse organs with tissues. Organs are assembled from the four basic types of tissues and have cells with specialized functions.
Line 99, 102 etc. – that authors should ensure that they use term “expression” in relation to genes only.
Line 499 - Please specify what are “hepatic sensory nerves” ?
The atuthors did not include nesfatin-1in their review. I find this a certain shortage especially that levels of nesfatin-1 are changed in ceratin liver-associated diseases (see. Başar et al., A novel appetite peptide, nesfatin-1 in patients with non-alcoholic fatty liver disease. Scand J Clin Lab Invest. 2012 Oct;72(6):479-83 and Solmaz et al., Nesfatin-1 alleviates extrahepatic cholestatic damage of liver in rats. Bosn J Basic Med Sci. 2016 Nov 10;16(4):247-253). Additonally, peripheral activity of nesfatin-1 as an agent regulating certain GIT functions is also known (please see Kras et al., Minireview: Peripheral Nesfatin-1 in Regulation of the Gut Activity-15 Years since the Discovery. Animals (Basel). 2022 Jan 1;12(1):101 for review). I think the authors should briefly address this issue in the Introduction as well as acknowledge these works.
Author Response
Overall, this is a well written and comprehensive review publication and offers a good overview on the role of different neuropeptides in liver normal and pathological functioning. However, some points need to be clarified.
My comments:
Line 84 - From histological point of view there are only four kinds of tissues: epithelial, connective, muscular and nervous. Therefore, such terms as “gastrointestinal tissue”, “placenta tissue, “liver tissue” or “neoplastic tissue” are not justified. The authors terribly confuse organs with tissues. Organs are assembled from the four basic types of tissues and have cells with specialized functions.
Line 99, 102 etc. – that authors should ensure that they use term “expression” in relation to genes only.
Thank you for this clarification. We replaced “tissue” with “organ” or “cells” in the entire text.
Line 499 - Please specify what are “hepatic sensory nerves” ?
Thank you for this question. We added a short explanation on lines 574-576, i.e. “hepatic sensory nerves which are nerve fibers of vagal or dorsal root/spinal origin that do not innervate directly hepatocytes, but the stroma surrounding the hepatic triades consisting of portal vein, hepatic artery and bile duct [166,167].”
The authors did not include nesfatin-1in their review. I find this a certain shortage especially that levels of nesfatin-1 are changed in ceratin liver-associated diseases (see. Başar et al., A novel appetite peptide, nesfatin-1 in patients with non-alcoholic fatty liver disease. Scand J Clin Lab Invest. 2012 Oct;72(6):479-83 and Solmaz et al., Nesfatin-1 alleviates extrahepatic cholestatic damage of liver in rats. Bosn J Basic Med Sci. 2016 Nov 10;16(4):247-253). Additonally, peripheral activity of nesfatin-1 as an agent regulating certain GIT functions is also known (please see Kras et al., Minireview: Peripheral Nesfatin-1 in Regulation of the Gut Activity-15 Years since the Discovery. Animals (Basel). 2022 Jan 1;12(1):101 for review). I think the authors should briefly address this issue in the Introduction as well as acknowledge these works.
Thank you for this suggestion. We added the following subsection on nesfatin-1 (lines 558-590):
- “Nesfatin-1
Nesfatin-1 was first identified in rat hypothalamus, as a polypeptide with anorexic effects, formed by enzymatic cleavage of nucleobindin-2 (NUCB2), a protein highly conserved from fish to mammals [152]. Like other neuropeptides with role in regulation of feeding behavior, nesfatin-1 is preponderant in ARC and PVN centers of hypothalamus and also outside CNS, especially in the GI tract having functions related to lipid metabolism, energy homeostasis and tissue regeneration after injuries [153]. Investigations on a possible role of nesfatin-1 in the liver started when a few clinical studies reported a significant reduction in serum nesfatin-1 level in patients with NAFLD [154] and obesity [155].
Investigations on molecular mechanisms of action of nesfatin-1, have not found specific receptors so far, but revealed the involvement of G-proteins and protein kinases C and A [152]. Evidence for a GPCR type of nesfatin-1 binding protein in the liver, was obtained from experiments with hepatocytes in vitro, whereby nesfatin-1 induced phosphorylation of AMPK, downregulation of lipogenic transcription factors PPARg and SREBP1 and significant reduction in lipid synthesis [156]. Moreover, it has been suggested that nesfatin-1 could act as an endogenous invers agonist of ghrelin receptor GHSR (growth hormone secretagogue receptor), since in HFD-fed mice, nesfatin-1 enhanced AKT level in the liver, which is a GHSR-dependent mechanism [157].
Based on reports about remarkable antioxidant, anti-inflammatory and antiapoptotic effects of treatment with nesfatin-1 in models of intestinal ulceration, studies on the influence of nesfatin-1 on cholestatic injury of the liver followed [158]. Thus, in a rat model of OJ (obstructive jaundice), it was demonstrated that nesfatin-1 treatment alleviated the OJ-caused liver damage, decreasing neutrophile infiltration, bile duct proliferation, edema and hepatocyte necrosis [158].
In conclusion, nesfatin-1 is a relatively novel neuropeptide and its characterization and study in relation to a multitude of physiological processes, including liver diseases, has just begun. The data reported so far from investigations of its role in the brain, liver, GI tract, cardiovascular system, and others, suggest that : i) nesfatin-1 is downregulated in diseases that incur cell apoptosis and necrosis, and its administration as replacement therapy could help cell and organ regeneration; ii) nesfatin-1 is upregulated above the normal level in diseases such as cancer for which strategies of blocking its effects could result in significant improvement of the present therapies.”
We also mentioned nesfatin-1 in the Introduction:
“This review is aimed to cover the most recent reports on hypothalamic neuropeptides that have impact on the hepatic system. While most of the neuropeptides discussed here have been known and studied for a long time, there are a few such as spexin and nesfatin-1 which were identified more recently, and have attracted a lot of attention for future research to develop newer, better therapies for liver diseases.”
Reviewer 3 Report
The growing epidemic of obesity and non-alcoholic fatty liver disease (NAFLD) calls for innovative approaches to target the pathophysiology. This review summarizes how different neuropeptides play a role in metabolic dysregulation and liver injury. Perhaps one way to better organize the review is to stratify each neuropeptide into pre-clinical and clinical data.
In lines 111-113, have the authors examined any studies where these findings can be translated into humans?
Additionally, in line 121, could the authors elaborate on how NPY affects lipid metabolism?
Are any of the neuropeptides involved in the signaling cascade leading to liver fibrosis?
Is there a therapeutic target for any of these neuropeptides that are currently in pre-clinical trials?
Most of the evolving targets for the treatment of NAFLD/NASH involve cell therapy, genetics, and immunotherapy, while others that regulate the immune response are in the early phases of clinical trials. Therefore, I suggest that the authors add more details and future directions to their discussion/conclusion section.
Line 691-692: Can the authors provide more specifics about newer therapies targeting neuropeptide receptors?
To enhance the clarity of the review, I recommend a one-liner summary point at the end of the discussion of each neuropeptide.
Author Response
Please see attachment
Author Response File: 
Author Response.docx
