Assessing the Functional Role of Leptin in Energy Homeostasis and the Stress Response in Vertebrates

Nesfatin-1, product of the precursor NEFA/nucleobindin2 (NUCB2), was initially identified as anorectic hypothalamic neuropeptide, acting in a leptin-independent manner. In addition to its central role in the control of energy homeostasis, evidence has mounted recently that nesfatin-1 is also produced in peripheral metabolic tissues, such as pancreas, adipose, and gut. Moreover, nesfatin-1 has been shown to participate in the control of body functions gated by whole-body energy homeostasis, including puberty onset. Yet, whether, as is the case for other metabolic neuropeptides, NUCB2/nesfatin-1 participates in the direct control of gonadal function remains unexplored. We document here for the first time the expression of NUCB2 mRNA in rat, mouse, and human testes, where NUCB2/nesfatin-1 protein was identified in interstitial mature Leydig cells. Yet in rats, NUCB2/nesfatin-1 became expressed in Sertoli cells upon Leydig cell elimination and was also detected in Leydig cell progenitors. Although NUCB2 mRNA levels did not overtly change in rat testis during pubertal maturation and after short-term fasting, NUCB2/nesfatin-1 content significantly increased along the puberty-to-adult transition and was markedly suppressed after fasting. In addition, testicular NUCB2/nesfatin-1 expression was up-regulated by pituitary LH, because hypophysectomy decreased, whereas human choriogonadotropin (super-agonist of LH receptors) replacement enhanced, NUCB2/nesfatin-1 mRNA and peptide levels. Finally, nesfatin-1 increased human choriogonadotropin-stimulated testosterone secretion by rat testicular explants ex vivo. Our data are the first to disclose the presence and functional role of NUCB2/nesfatin-1 in the testis, where its expression is regulated by developmental, metabolic, and hormonal cues as well as by Leydig cell-derived factors. Our observations expand the reproductive dimension of nesfatin-1, which may operate directly at the testicular level to link energy homeostasis, puberty onset, and gonadal function.

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Functional Role of Suppressor of Cytokine Signaling 3 Upregulation in Hypothalamic Leptin Resistance and Long-Term Energy Homeostasis

Diabetes ◽

10.2337/db09-1024 ◽

2010 ◽

Vol 59 (4) ◽

pp. 894-906 ◽

Cited By ~ 103

Author(s):

A. S. Reed ◽

E. K. Unger ◽

L. E. Olofsson ◽

M. L. Piper ◽

M. G. Myers ◽

...

Keyword(s):

Functional Role ◽

Energy Homeostasis ◽

Leptin Resistance ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Term Energy

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Elucidating the functional role of Mycobacterium smegmatis recX in stress response

Scientific Reports ◽

10.1038/s41598-019-47312-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Deepika Prasad ◽

Divya Arora ◽

Vinay Kumar Nandicoori ◽

K. Muniyappa

Keyword(s):

Stress Response ◽

Mycobacterium Smegmatis ◽

Functional Role

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Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells

Gut ◽

10.1136/gutjnl-2019-318483 ◽

2019 ◽

Vol 69 (3) ◽

pp. 578-590 ◽

Cited By ~ 13

Author(s):

Nick Powell ◽

Eirini Pantazi ◽

Polychronis Pavlidis ◽

Anastasia Tsakmaki ◽

Katherine Li ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Stress Response ◽

Epithelial Cells ◽

Er Stress ◽

Functional Role ◽

Chronic Colitis ◽

Colonic Epithelial Cells ◽

Interleukin 22 ◽

Er Stress Response

ObjectiveThe functional role of interleukin-22 (IL22) in chronic inflammation is controversial, and mechanistic insights into how it regulates target tissue are lacking. In this study, we evaluated the functional role of IL22 in chronic colitis and probed mechanisms of IL22-mediated regulation of colonic epithelial cells.DesignTo investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial cells, we employed a three-dimentional mini-gut epithelial organoid system, in vivo disease models and transcriptomic datasets in human IBD.ResultsAs well as inducing transcriptional modules implicated in antimicrobial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional programme in colonic epithelial cells. In the colon of patients with active colonic Crohn’s disease (CD), there was enrichment of IL22-responsive transcriptional modules and ER stress response modules. Strikingly, in an IL22-dependent model of chronic colitis, targeting IL22 alleviated colonic epithelial ER stress and attenuated colitis. Pharmacological modulation of the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response.ConclusionsOur data challenge perceptions of IL22 as a predominantly beneficial cytokine in IBD and provide novel insights into the molecular mechanisms of IL22-mediated pathogenicity in chronic colitis. Targeting IL22-regulated pathways and alleviating colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis.Trial registration numberNCT02749630.

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Functional role of histone variant Htz1 in the stress response to oleate in Saccharomyces cerevisiae

Bioscience Reports ◽

10.1042/bsr20150114 ◽

2015 ◽

Vol 35 (4) ◽

Cited By ~ 1

Author(s):

Hongde Liu ◽

Guanghui Li ◽

Lingjie Liu ◽

Yakun Wan

Keyword(s):

Saccharomyces Cerevisiae ◽

Stress Response ◽

Functional Role ◽

Histone Variant ◽

Citrate Cycle ◽

Multicopy Suppressor ◽

Nucleosome Dynamics

In response to oleate stress in Saccharomyces cerevisiaes, Histone Two A Z1 (Htz1) undergoes a global redistribution during the glucose-oleate shift. The number of Htz1-bound genes increases, but the number of Htz1-bound ribosome genes decreases with stress. Citrate cycle-associated genes are enhanced and ribosome genes are repressed. Nucleosome dynamics are coupled with Htz1-binding changes upon stress. Multicopy suppressor of SNF1 protein 2 (Msn2) acts an important role in response to the oleate stress. We highlight the dynamics of Htz1 in the oleate stress.

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