Transcriptional study reveals a potential leptin-dependent gene regulatory network in zebrafish brain

Abstract

The signal mediated by leptin hormone and its receptor is a major regulator of body weight, food intake and metabolism. In mammals and many teleost fish species, leptin has an anorexigenic role and inhibits food intake by influencing the appetite centres in the hypothalamus. However, the regulatory connections between leptin and downstream genes mediating its appetite-regulating effects are still not fully explored in teleost fish. In this study, we used a loss of function leptin receptor zebrafish mutant and real-time quantitative PCR to assess brain expression patterns of several previously identified anorexigenic genes downstream of leptin signal under different feeding conditions (normal feeding, 7-day fasting, 2 and 6-h refeeding). These downstream factors include members of cart genes, crhb and gnrh2, as well as selected genes co-expressed with them based on a zebrafish co-expression database. Here, we found a potential gene expression network (GRN) comprising the abovementioned genes by a stepwise approach of identifying co-expression modules and predicting their upstream regulators. Among the transcription factors (TFs) predicted as potential upstream regulators of this GRN, we found expression pattern of sp3a to be correlated with transcriptional changes of the downstream gene network. Interestingly, the expression and transcriptional activity of Sp3 orthologous gene in mammals have already been implicated to be under the influence of leptin signal. These findings suggest a potentially conserved regulatory connection between leptin and sp3a, which is predicted to act as a transcriptional driver of a downstream gene network in the zebrafish brain.

Molecular Characterization and Expression Pattern of leptin in Yellow Cheek Carp (Elopichthys bambusa) and Its Transcriptional Changes in Response to Fasting and Refeeding

“…In fish, the endocrine signals in the hypothalamus region that influence the brain's regulation of food intake could be triggered by different nutritional and metabolic conditions [45,46]. Genes that control these endocrine signals (leptin is one of them) play an important role in appetite regulation [47].…”

Appetite regulating genes in zebrafish gut; a gene expression study

“…This also suggests that a recently found gene regulatory network (GRN) in zebrafish brain, consisting leptin signal and sp1 transcription factor as upstream regulators of cart genes, i.e. lepr-sp1-cart axis, does not exist in the gut [ 107 ]. Cart genes are shown to have conserved anorexigenic role in teleosts [ 30 ], including zebrafish [ 47 , 48 ].…”

A pituitary gene network linking vgll3 to regulators of sexual maturation in male Atlantic salmon

“…We followed a previously established approach for GRN identification (Ahi et al, 2021(Ahi et al, , 2015Ahi and Sefc, 2018;Pohl et al, 2021) using zebrafish co-expression data available at COXPRESdb (http://coxpresdb.jp/) version 7.0 (Obayashi et al, 2019). To do this, we first selected the 10 genes with the highest co-expression values with jun and sf1 (nr5a1b).…”

“…Sf1 is also a known direct upstream regulator of both Lhb and Fshb and its transcriptional activity is again under the influence of GnRH1 in mammals (Haisenleder et al, 1996;Kaiser et al, 2000;Keri and Nilson, 1996) The abovementioned findings in mammals raise the questions how jun and sf1 are induced in the pituitary of Atlantic salmon in the absence of gnrh1 and also how their transcriptional induction is linked to the vgll3*E allele. Here, we conduct a stepwise approach established in different teleost fish taxa (Ahi et al, 2021(Ahi et al, , 2015Ahi and Sefc, 2018;Pohl et al, 2021) that combines knowledge-based and de novo methods with gene expression analysis to identify gene regulatory network(s), or GRNs, linking vgll3 function to differential expression of jun and sf1 in the absence of gnrh1 in the pituitary of Atlantic salmon.…”