LETTER TO THE EDITOR
Journal of
Is the Reg3a (HIP/PAP) Protein Really an Obesogenic Factor?
Cellular Physiology
PATRICK GONZALEZ, NICOLAS MONIAUX, CHRISTIAN BR ECHOT, AND JAMILA FAIVRE* INSERM UMR-1193, Paul-Brousse University Hospital, University Paris Saclay, Villejuif, France To the Editor, We would like to point out an internal inconsistency in the data presented by V. Secq et al. in the article entitled “PAP/HIP protein is an obesogenic factor“ published in the February 2014 issue of “Journal of Cellular Physiology,“ which cast serious doubt on the validity of the statement serving as the title of the article. We, and others, including J. Iovanna and his collaborators, have long shown that the C-type lectin PAP/HIP (also known as HIP/ PAP or Reg3a) has anti-inflammatory and antioxidant activities in a number of cell types, among which pancreatic cells, hepatocytes, and neurons (Gironella et al., 2005; Closa et al., 2007; Moniaux et al., 2011; Kapur et al., 2012; Haldipur et al., 2014) and that, therefore, it might help cure, or prevent, inflammatory and metabolic diseases. Given its envisaged clinical uses, the question of whether PAP/HIP significantly modifies metabolism toward weight increase is essential and must be subjected to rigorous scrutiny. We have been working on the PAP/HIP protein and animal models similar to those used by V. Secq et al. for years without observing any obesogenic effect. We were, therefore, surprised by the title of V. Secq et al.’s article. After looking closely at the results presented in the article, we found that—in addition to being quite minimalist (very small cohorts, no data on fat mass gain, energy expenditure, food intake, insulin resistance)—these results are vitiated by a serious discrepancy. The claim that PAP/HIP is obesogenic is only directly supported by the data displayed in Figure 1. In this figure, the authors report a spontaneous increase in body weight in a cohort of 20 PAP/HIP-transgenic (TG) mice between 6 and 27 weeks of life compared to 13 wild-type control mice, all the animals being on normal diet (Fig. 1 Fig. 1A). Conversely, PAP/ HIP-deficient (KO) mice appear to be slimmer than control ones (Fig. 1C). Finally, the authors report a positive statistical correlation between increases in body weight and PAP/HIP serum level in 20 TG-mice aged 15 weeks (Fig. 1D). The text does not explicitly state that the same cohort of 20 mice was used for Figure 1A and D, but this is likely. In any case, the experimental conditions were supposed to be the same and should lead to the same results within experimental error.
However, the data of Figure 1A and D do not coincide. The average body weight value of TG-mice at 15 weeks according to Figure 1A is of 41.5 4.0 g, while most of the individual weights presented in Figure 1D are below this value. We performed a careful estimate of the average body weight from the data of Figure 1D, which yielded 35 2.0 g. The discrepancy between Figure 1A and D on this point is thus a clear-cut one. It is potentially fatal to the authors’ conclusion that PAP/HIP is obesogenic since the body weight value of TGmice at 15 weeks according to Figure 1D (35 2.0 g) does not significantly differ from that of control mice according to Figure 1A (31 2.0 g). In addition, we would like to stress that the meaning of a phenotypic comparison between TG-mice (Figure 1A) and KO-mice (Figure 1C) is not as obvious as the authors seem to think. Transgenesis and knockout processes are not exact opposites of one another: TG-mice overexpress human Reg3a in hepatocytes, whereas the knockout is somatic and does not hit Reg3a, but its murine homolog Reg3b. So, the emaciation of the KO mice observed in this study is in fact essentially unexplained. Thus, in total, the article provides no conclusive evidence to support the claim that PAP/HIP is obesogenic. We hope that these critical remarks on the results provided by Secq et al. will be deemed suitable for publication by the “Journal of Cellular Physiology.“ Literature Cited Gironella M, Iovanna JL, Sans M, Gil F, Pe~nalva M, Closa D, Miquel R, Pique JM, Panes J. 2005. Anti-inflammatory effects of pancreatitis associated protein in inflammatory bowel disease. Gut 54:1244–1253. Closa D, Motoo Y, Iovanna JL. 2007. Pancreatitis-associated protein: From a lectin to an antiinflammatory cytokine. World J Gastroenterol 13:170–174.Review. Moniaux N, Song H, Darnaud M, Garbin K, Gigou M, Mitchell C, Samuel D, Jamot L, Amouyal P, Amouyal G, Brechot C, Faivre J. 2011. Human hepatocarcinoma-intestine-pancreas/ pancreatitis-associated protein cures fas-induced acute liver failure in mice by attenuating free-radical damage in injured livers. Hepatology 53:618–627. Kapur R, Hùjfeldt TW, Hùjfeldt TW, Rùnn SG, Karlsen AE, Heller RS. 2012. Short-term effects of INGAP and Reg family peptides on the appearance of small b-cells clusters in non- diabetic mice. Islets 4:40–48. Haldipur P, Dupuis N, Degos V, Moniaux N, Chhor V, Rasika S, Schwendimann L, le Charpentier T, Rougier E, Amouyal P, Amouyal G, Dournaud P, Brechot C, El Ghouzzi, V, Faivre J, Fleiss B, Mani S, Gressens P. 2014. HIP/PAP prevents excitotoxic neuronal death and promotes plasticity. Ann Clin Transl Neurol 1:739–754.
*Correspondence to: Jamila Faivre, INSERM UMR-1193, PaulBrousse University Hospital, University Paris Saclay, Villejuif 94800, France. E-mail: [email protected] Manuscript Received: 30 April 2015 Manuscript Accepted: 13 May 2015 Accepted manuscript online in Wiley Online Library (wileyonlinelibrary.com): 19 June 2015. DOI: 10.1002/jcp.25046
© 2 0 1 5 W I L E Y P E R I O D I C A L S , I N C .
1
Journal of
Is the Reg3a (HIP/PAP) Protein Really an Obesogenic Factor?
Cellular Physiology
PATRICK GONZALEZ, NICOLAS MONIAUX, CHRISTIAN BR ECHOT, AND JAMILA FAIVRE* INSERM UMR-1193, Paul-Brousse University Hospital, University Paris Saclay, Villejuif, France To the Editor, We would like to point out an internal inconsistency in the data presented by V. Secq et al. in the article entitled “PAP/HIP protein is an obesogenic factor“ published in the February 2014 issue of “Journal of Cellular Physiology,“ which cast serious doubt on the validity of the statement serving as the title of the article. We, and others, including J. Iovanna and his collaborators, have long shown that the C-type lectin PAP/HIP (also known as HIP/ PAP or Reg3a) has anti-inflammatory and antioxidant activities in a number of cell types, among which pancreatic cells, hepatocytes, and neurons (Gironella et al., 2005; Closa et al., 2007; Moniaux et al., 2011; Kapur et al., 2012; Haldipur et al., 2014) and that, therefore, it might help cure, or prevent, inflammatory and metabolic diseases. Given its envisaged clinical uses, the question of whether PAP/HIP significantly modifies metabolism toward weight increase is essential and must be subjected to rigorous scrutiny. We have been working on the PAP/HIP protein and animal models similar to those used by V. Secq et al. for years without observing any obesogenic effect. We were, therefore, surprised by the title of V. Secq et al.’s article. After looking closely at the results presented in the article, we found that—in addition to being quite minimalist (very small cohorts, no data on fat mass gain, energy expenditure, food intake, insulin resistance)—these results are vitiated by a serious discrepancy. The claim that PAP/HIP is obesogenic is only directly supported by the data displayed in Figure 1. In this figure, the authors report a spontaneous increase in body weight in a cohort of 20 PAP/HIP-transgenic (TG) mice between 6 and 27 weeks of life compared to 13 wild-type control mice, all the animals being on normal diet (Fig. 1 Fig. 1A). Conversely, PAP/ HIP-deficient (KO) mice appear to be slimmer than control ones (Fig. 1C). Finally, the authors report a positive statistical correlation between increases in body weight and PAP/HIP serum level in 20 TG-mice aged 15 weeks (Fig. 1D). The text does not explicitly state that the same cohort of 20 mice was used for Figure 1A and D, but this is likely. In any case, the experimental conditions were supposed to be the same and should lead to the same results within experimental error.
However, the data of Figure 1A and D do not coincide. The average body weight value of TG-mice at 15 weeks according to Figure 1A is of 41.5 4.0 g, while most of the individual weights presented in Figure 1D are below this value. We performed a careful estimate of the average body weight from the data of Figure 1D, which yielded 35 2.0 g. The discrepancy between Figure 1A and D on this point is thus a clear-cut one. It is potentially fatal to the authors’ conclusion that PAP/HIP is obesogenic since the body weight value of TGmice at 15 weeks according to Figure 1D (35 2.0 g) does not significantly differ from that of control mice according to Figure 1A (31 2.0 g). In addition, we would like to stress that the meaning of a phenotypic comparison between TG-mice (Figure 1A) and KO-mice (Figure 1C) is not as obvious as the authors seem to think. Transgenesis and knockout processes are not exact opposites of one another: TG-mice overexpress human Reg3a in hepatocytes, whereas the knockout is somatic and does not hit Reg3a, but its murine homolog Reg3b. So, the emaciation of the KO mice observed in this study is in fact essentially unexplained. Thus, in total, the article provides no conclusive evidence to support the claim that PAP/HIP is obesogenic. We hope that these critical remarks on the results provided by Secq et al. will be deemed suitable for publication by the “Journal of Cellular Physiology.“ Literature Cited Gironella M, Iovanna JL, Sans M, Gil F, Pe~nalva M, Closa D, Miquel R, Pique JM, Panes J. 2005. Anti-inflammatory effects of pancreatitis associated protein in inflammatory bowel disease. Gut 54:1244–1253. Closa D, Motoo Y, Iovanna JL. 2007. Pancreatitis-associated protein: From a lectin to an antiinflammatory cytokine. World J Gastroenterol 13:170–174.Review. Moniaux N, Song H, Darnaud M, Garbin K, Gigou M, Mitchell C, Samuel D, Jamot L, Amouyal P, Amouyal G, Brechot C, Faivre J. 2011. Human hepatocarcinoma-intestine-pancreas/ pancreatitis-associated protein cures fas-induced acute liver failure in mice by attenuating free-radical damage in injured livers. Hepatology 53:618–627. Kapur R, Hùjfeldt TW, Hùjfeldt TW, Rùnn SG, Karlsen AE, Heller RS. 2012. Short-term effects of INGAP and Reg family peptides on the appearance of small b-cells clusters in non- diabetic mice. Islets 4:40–48. Haldipur P, Dupuis N, Degos V, Moniaux N, Chhor V, Rasika S, Schwendimann L, le Charpentier T, Rougier E, Amouyal P, Amouyal G, Dournaud P, Brechot C, El Ghouzzi, V, Faivre J, Fleiss B, Mani S, Gressens P. 2014. HIP/PAP prevents excitotoxic neuronal death and promotes plasticity. Ann Clin Transl Neurol 1:739–754.
*Correspondence to: Jamila Faivre, INSERM UMR-1193, PaulBrousse University Hospital, University Paris Saclay, Villejuif 94800, France. E-mail: [email protected] Manuscript Received: 30 April 2015 Manuscript Accepted: 13 May 2015 Accepted manuscript online in Wiley Online Library (wileyonlinelibrary.com): 19 June 2015. DOI: 10.1002/jcp.25046
© 2 0 1 5 W I L E Y P E R I O D I C A L S , I N C .
1
