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. 2023 Oct 14;24(20):15190.
doi: 10.3390/ijms242015190.

Neurolysin Knockout Mice in a Diet-Induced Obesity Model

Bruna Caprioli  1 , Rosangela A S Eichler  1 , Renée N O Silva  1 , Luiz Felipe Martucci  1 , Patricia Reckziegel  2 , Emer S Ferro  1
Affiliations

Neurolysin Knockout Mice in a Diet-Induced Obesity Model

Bruna Caprioli et al. Int J Mol Sci. .

Abstract

Neurolysin oligopeptidase (E.C.3.4.24.16; Nln), a member of the zinc metallopeptidase M3 family, was first identified in rat brain synaptic membranes hydrolyzing neurotensin at the Pro-Tyr peptide bond. The previous development of C57BL6/N mice with suppression of Nln gene expression (Nln-/-), demonstrated the biological relevance of this oligopeptidase for insulin signaling and glucose uptake. Here, several metabolic parameters were investigated in Nln-/- and wild-type C57BL6/N animals (WT; n = 5-8), male and female, fed either a standard (SD) or a hypercaloric diet (HD), for seven weeks. Higher food intake and body mass gain was observed for Nln-/- animals fed HD, compared to both male and female WT control animals fed HD. Leptin gene expression was higher in Nln-/- male and female animals fed HD, compared to WT controls. Both WT and Nln-/- females fed HD showed similar gene expression increase of dipeptidyl peptidase 4 (DPP4), a peptidase related to glucagon-like peptide-1 (GLP-1) metabolism. The present data suggest that Nln participates in the physiological mechanisms related to diet-induced obesity. Further studies will be necessary to better understand the molecular mechanism responsible for the higher body mass gain observed in Nln-/- animals fed HD.

Keywords: adipose tissue; diet-induced obesity; glucagon-like peptide-1; intracellular peptides; leptin; neurolysin; neurotensin; obesity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Weight gain of animals over seven weeks. A and B: body mass week gain in male (A) or female (B) mice, WT or Nln-/-, fed SD or HD diet. C and D: the final body mass was subtracted from the initial body mass (body mass gain) of male (C) or female (D) mice, WT or Nln-/-, fed SD or HD. (A–D): *, p < 0.05 between WT SD vs. WT HD or Nln-/- SD vs. Nln-/- HD; #, p < 0.05 between WT SD vs. Nln-/- SD or WT HD vs. Nln-/- HD. Statistical analyses were performed using two-way ANOVA with the post-hoc Holm–Sidak test. Data are presented as mean ± SEM. n = 5–8 animals per group. Each individual group (WT, SD; WT, HD; Nln-/-, SD; Nln-/-, HD) was indicated with a specific symbol shown on the figure legend.
Figure 2
Figure 2
Glucose tolerance test (GTT) in male (A,C) or female (B,D) animals. (A,B), glycemic curves over the 120 min interval, (C,D), the area under the glycemic curves of the WT or Nln-/- animals fed SD or HD. Intraperitoneal administration of glucose (2 g/Kg) was followed by blood glucose measurement with AccuCheck glycostrip (Roche, São Paulo, Brazil), at 15, 30, 60, 90 and 120 min. A sample collected and evaluated before glucose administration was considered as fasting blood glucose (time 0). A–D: *, p < 0.05 between WT SD vs. WT HD or Nln-/- SD vs. Nln-/- HD; #, p < 0.05 between WT SD vs. Nln-/- SD or WT HD vs. Nln-/- HD. Statistical analyses were performed using two-way ANOVA with the post-hoc Holm–Sidak test. Data are presented as mean ± SEM. n = 5–8 animals per group.
Figure 3
Figure 3
Quantitative assessment of plasma insulin by ELISA. (A,B): respectively, male and female animals. A and B: *, p < 0.05 between WT SD vs. WT HD or Nln-/- SD vs. Nln-/- HD; #, p < 0.05 between WT SD vs. Nln-/- SD or WT HD vs. Nln-/- HD. Statistical analyses were performed using two-way ANOVA with the post-hoc Holm–Sidak test. Data are presented as mean ± SEM. n = 5–8 animals per group.
Figure 4
Figure 4
Insulin tolerance test (ITT) was performed in WT and Nln-/-, male (A,C) and female (B,D) animals fed SD or HD. Intraperitoneal insulin administration was followed by blood glucose measurement after 4, 8, 12 and 16 min (A,B). Note that only HD-fed male Nln-/- animals showed statistically significant reduced insulin sensitivity (C). Nln-/- male animals fed SD have a tendency to have greater insulin sensitivity, which was not seen as statistically significant. (A–D): *, p < 0.05 between WT SD vs. WT HD or Nln-/- SD vs. Nln-/- HD. Statistical analyses were performed using two-way ANOVA with the post-hoc Holm–Sidak test. Data are presented as mean ± SEM. n = 5–8 animals per group.
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