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Cited by 254Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesPeroxisome Proliferator-Activated Receptors

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Mechanisms of the Anti-Obesity Effects of Oxytocin in Diet-Induced Obese Rats

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Deblon, Nicolas, Veyrat-Durebex, Christelle, Bourgoin, Lucie, Caillon, Aurélie, Bussier, Anne-Lise, Petrosino, Stefania, Piscitelli, Fabiana, Legros, Jean-Jacques, Geenen, Vincent, Foti, Michelangelo, Wahli, Walter, Di Marzo, Vincenzo, Rohner-Jeanrenaud, Françoise·2011·PLoS ONE
DOI 10.1371/journal.pone.0025565PMC PMC3181274
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Abstract

Apart from its role during labor and lactation, oxytocin is involved in several other functions. Interestingly, oxytocin- and oxytocin receptor-deficient mice develop late-onset obesity with normal food intake, suggesting that the hormone might exert a series of beneficial metabolic effects. This was recently confirmed by data showing that central oxytocin infusion causes weight loss in diet-induced obese mice. The aim of the present study was to unravel the mechanisms underlying such beneficial effects of oxytocin. Chronic central oxytocin infusion was carried out in high fat diet-induced obese rats. Its impact on body weight, lipid metabolism and insulin sensitivity was determined. We observed a dose-dependent decrease in body weight gain, increased adipose tissue lipolysis and fatty acid β-oxidation, as well as reduced glucose intolerance and insulin resistance. The additional observation that plasma oxytocin levels increased upon central infusion suggested that the hormone might affect adipose tissue metabolism by direct action. This was demonstrated using in vitro, ex vivo, as well as in vivo experiments. With regard to its mechanism of action in adipose tissue, oxytocin increased the expression of stearoyl-coenzyme A desaturase 1, as well as the tissue content of the phospholipid precursor, N-oleoyl-phosphatidylethanolamine, the biosynthetic precursor of the oleic acid-derived PPAR-alpha activator, oleoylethanolamide. Because PPAR-alpha regulates fatty acid β-oxidation, we hypothesized that this transcription factor might mediate the oxytocin effects. This was substantiated by the observation that, in contrast to its effects in wild-type mice, oxytocin infusion failed to induce weight loss and fat oxidation in PPAR-alpha-deficient animals. Altogether, these results suggest that oxytocin administration could represent a promising therapeutic approach for the treatment of human obesity and type 2 diabetes.

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Figure 1 Central OT infusion causes body weight loss independently from changes in food intake. The measurements were performed over a 14-day experimental period (weeks 5 through 7 of a high fat diet): (A) Cumulative body weight changes; (B) cumulative food intake; (C) food efficiency ((body weight gain/cumulative food intake over the 2 week experimental period) x 100). Filled bars: i.c.v. saline–infused controls; open bars: i.c.v. OT-infused rats (1.6 nmol/d). Values are mean ± SEM of 6 to 7 rats/group. *P<0.05 compared to controls.
Figure 1 Central OT infusion causes body weight loss independently from changes in food intake. The measurements were performed over a 14-day experimental period (weeks 5 through 7 of a high fat diet): (A) Cumulative body weight changes; (B) cumulative food intake; (C) food efficiency ((body weight gain/cumulative food intake over the 2 week experimental period) x 100). Filled bars: i.c.v. saline–infused controls; open bars: i.c.v. OT-infused rats (1.6 nmol/d). Values are mean ± SEM of 6 to 7 rats/group. *P<0.05 compared to controls.CC BY · PubMed Central
Figure 2 Central OT infusion stimulates lipid metabolism. The following analyses were performed on epididymal white adipose tissue (eWAT) of i.c.v. saline–infused controls (filled bars) and i.c.v. OT-infused rats (1.6 nmol/d; open bars): (A) mRNA expression of enzymes related to lipid metabolism; (B) Western blot analysis of HSL standardized to actin expression; (C) mRNA expression of PPAR-alpha and PPAR-alpha target genes; (D) Scd1 mRNA expression; (E) Oleoylethanolamide (OEA) content in eWAT. Values are mean ± SEM of 6 to 7 rats/group. *P<0.05, **P<0.01 compared to controls.
Figure 2 Central OT infusion stimulates lipid metabolism. The following analyses were performed on epididymal white adipose tissue (eWAT) of i.c.v. saline–infused controls (filled bars) and i.c.v. OT-infused rats (1.6 nmol/d; open bars): (A) mRNA expression of enzymes related to lipid metabolism; (B) Western blot analysis of HSL standardized to actin expression; (C) mRNA expression of PPAR-alpha and PPAR-alpha target genes; (D) Scd1 mRNA expression; (E) Oleoylethanolamide (OEA) content in eWAT. Values are mean ± SEM of 6 to 7 rats/group. *P<0.05, **P<0.01 compared to controls.CC BY · PubMed Central
Figure 3 Dose-dependency of the effect of central OT infusion. After 14-day treatments (weeks 5 to 7 of high fat diet, 45% fat), the following measurements were made in i.c.v. saline–infused controls (filled bars), i.c.v. OT-infused rats (16 nmol/d; open bars), and i.c.v. saline-infused pair-fed (PF) controls (hatched bars): (A) Delta body weight gain; (B) cumulative food intake; (C) plasma leptin levels; (D) respiratory exchange ratio (VO2: VCO2); (E) Scd1 mRNA expression; (F) OEA content in epididymal white adipose tissue (eWAT); and (G) mRNA expression of lipid metabolism-related enzymes in eWAT. Values are mean ± SEM of 6 to 7 animals/group. *P<0.05, **P<0.01, ***P<0.005, compared to controls.
Figure 3 Dose-dependency of the effect of central OT infusion. After 14-day treatments (weeks 5 to 7 of high fat diet, 45% fat), the following measurements were made in i.c.v. saline–infused controls (filled bars), i.c.v. OT-infused rats (16 nmol/d; open bars), and i.c.v. saline-infused pair-fed (PF) controls (hatched bars): (A) Delta body weight gain; (B) cumulative food intake; (C) plasma leptin levels; (D) respiratory exchange ratio (VO2: VCO2); (E) Scd1 mRNA expression; (F) OEA content in epididymal white adipose tissue (eWAT); and (G) mRNA expression of lipid metabolism-related enzymes in eWAT. Values are mean ± SEM of 6 to 7 animals/group. *P<0.05, **P<0.01, ***P<0.005, compared to controls.CC BY · PubMed Central
Figure 4 Central OT infusion induces hypothalamic OT synthesis and release into the bloodstream. The following parameters were measured at the end of 14-day treatments with two doses of i.c.v. OT infusion: (A) Oxytocin expression (Oxt) in rat hypothalamus; (B) plasma OT levels in saline–infused controls (filled bars) and OT-infused rats (1.6 nmol/d, open bars). Values are mean ± SEM of 6 to 7 rats/group. *P<0.05 compared to controls; (C) Oxytocin expression (Oxt) in rat hypothalamus; (D) plasma OT levels in saline–infused controls (filled bars), OT-infused rats (16 nmol/d, open bars) and pair-fed (PF) controls (hatched bars). Values are mean ± SEM of 6 to 7 rats/group. *P<0.05 compared to controls.
Figure 4 Central OT infusion induces hypothalamic OT synthesis and release into the bloodstream. The following parameters were measured at the end of 14-day treatments with two doses of i.c.v. OT infusion: (A) Oxytocin expression (Oxt) in rat hypothalamus; (B) plasma OT levels in saline–infused controls (filled bars) and OT-infused rats (1.6 nmol/d, open bars). Values are mean ± SEM of 6 to 7 rats/group. *P<0.05 compared to controls; (C) Oxytocin expression (Oxt) in rat hypothalamus; (D) plasma OT levels in saline–infused controls (filled bars), OT-infused rats (16 nmol/d, open bars) and pair-fed (PF) controls (hatched bars). Values are mean ± SEM of 6 to 7 rats/group. *P<0.05 compared to controls.CC BY · PubMed Central
Figure 5 OT directly affects lipid metabolism. (A) Lipid metabolism-related enzyme expression in differentiated 3T3-L1 adipocytes (24 h saline or 5 µM OT). Values are mean ± SEM of three independent experiments. *P<0.05, **P<0.01 compared to controls. (B–C) Epididymal fat pads from lean Wistar rats were incubated at 37°C in the presence of Krebs-Ringer-Hepes buffer containing 2% FA-free BSA and 0.1% glucose. After 4 h of incubation in the presence of either saline or OT (10 nM), the amount of (B) glycerol and (C) free fatty acid released in the medium was measured. Values are mean ± SEM of three independent experiments. (D–F) Measurements performed over the 14-day s.c. saline or OT treatment in lean rats fed a standard diet: (D) Cumulative body weight gain; (E) cumulative food intake; (F) changes in body composition between days 0 and 10 of treatment. Saline–infused controls (black circles, filled bars), OT-infused rats (50 nmol/d; white diamonds, open bars), and saline-infused PF controls (black triangles, hatched bars). Values are mean ± SEM of 6 to 7 rats/group. *P<0.05.
Figure 5 OT directly affects lipid metabolism. (A) Lipid metabolism-related enzyme expression in differentiated 3T3-L1 adipocytes (24 h saline or 5 µM OT). Values are mean ± SEM of three independent experiments. *P<0.05, **P<0.01 compared to controls. (B–C) Epididymal fat pads from lean Wistar rats were incubated at 37°C in the presence of Krebs-Ringer-Hepes buffer containing 2% FA-free BSA and 0.1% glucose. After 4 h of incubation in the presence of either saline or OT (10 nM), the amount of (B) glycerol and (C) free fatty acid released in the medium was measured. Values are mean ± SEM of three independent experiments. (D–F) Measurements performed over the 14-day s.c. saline or OT treatment in lean rats fed a standard diet: (D) Cumulative body weight gain; (E) cumulative food intake; (F) changes in body composition between days 0 and 10 of treatment. Saline–infused controls (black circles, filled bars), OT-infused rats (50 nmol/d; white diamonds, open bars), and saline-infused PF controls (black triangles, hatched bars). Values are mean ± SEM of 6 to 7 rats/group. *P<0.05.CC BY · PubMed Central
Figure 6 Peripheral OT effects in HFD fed rats. The measurements were performed over a 14-day experimental period (weeks 5 through 7 of a high fat diet) in s.c. saline–infused controls (black circles, filled bars), s.c. OT-infused rats (50 nmol/d; white diamonds, open bars), and s.c. saline-infused PF controls (black triangles, hatched bars): (A) Cumulative body weight gain; (B) cumulative food intake; (C) changes in body composition between days 0 and 10 of treatment. (D) Plasma OT levels; (E) NOPE and (F) OEA content in eWAT. Values are mean ± SEM of 7 to 8 rats/group. *P<0.05, **P<0.01 compared to controls.
Figure 6 Peripheral OT effects in HFD fed rats. The measurements were performed over a 14-day experimental period (weeks 5 through 7 of a high fat diet) in s.c. saline–infused controls (black circles, filled bars), s.c. OT-infused rats (50 nmol/d; white diamonds, open bars), and s.c. saline-infused PF controls (black triangles, hatched bars): (A) Cumulative body weight gain; (B) cumulative food intake; (C) changes in body composition between days 0 and 10 of treatment. (D) Plasma OT levels; (E) NOPE and (F) OEA content in eWAT. Values are mean ± SEM of 7 to 8 rats/group. *P<0.05, **P<0.01 compared to controls.CC BY · PubMed Central
Figure 7 PPAR-alpha mediates peripheral OT effects. (A) Cumulative body weight gain after 3 days of s.c. saline or OT treatment in PPAR-alpha KO and wild-type (WT) mice. (B) eWAT mRNA expression of PPAR-alpha target genes and Scd1 in PPAR-alpha KO and WT mice. Values are mean ± SEM of 5 animals/group. *P<0.05 compared to controls.
Figure 7 PPAR-alpha mediates peripheral OT effects. (A) Cumulative body weight gain after 3 days of s.c. saline or OT treatment in PPAR-alpha KO and wild-type (WT) mice. (B) eWAT mRNA expression of PPAR-alpha target genes and Scd1 in PPAR-alpha KO and WT mice. Values are mean ± SEM of 5 animals/group. *P<0.05 compared to controls.CC BY · PubMed Central
Figure 8 Central and peripheral OT infusion protects against high fat diet-induced insulin resistance. I.c.v. saline- (black circles) or OT- (1.6 nmol/d; white diamonds) infused rats received: glucose tolerance tests (1.5 g/kg) before (black triangles, dashed line; 3 weeks of HFD; n = 16 rats) or after infusions (7 weeks of HFD; 14-day i.c.v. infusions; n = 6 for each treatment group): (A) delta glucose and (B) delta insulin; One-way ANOVA: *P<0.05 compared to black triangles; ‡P<0.05 compared to black circles. (C–D) Euglycemic-hyperinsulinemic clamps performed at the end of 14-day treatments: (C) Glucose infusion rate (GIR) of i.c.v. saline- (filled bars) or OT- (1.6 nmol/d; open bars) infused rats. Values are mean ± SEM of 6 to 7 rats/group. *P<0.05 compared to controls. (D) GIR of s.c. saline–infused controls (filled bars), OT-infused rats (50 nmol/d; open bars), and saline-infused PF controls (hatched bars). Values are mean ± SEM of 6 to 7 rats/group. *P<0.05.
Figure 8 Central and peripheral OT infusion protects against high fat diet-induced insulin resistance. I.c.v. saline- (black circles) or OT- (1.6 nmol/d; white diamonds) infused rats received: glucose tolerance tests (1.5 g/kg) before (black triangles, dashed line; 3 weeks of HFD; n = 16 rats) or after infusions (7 weeks of HFD; 14-day i.c.v. infusions; n = 6 for each treatment group): (A) delta glucose and (B) delta insulin; One-way ANOVA: *P<0.05 compared to black triangles; ‡P<0.05 compared to black circles. (C–D) Euglycemic-hyperinsulinemic clamps performed at the end of 14-day treatments: (C) Glucose infusion rate (GIR) of i.c.v. saline- (filled bars) or OT- (1.6 nmol/d; open bars) infused rats. Values are mean ± SEM of 6 to 7 rats/group. *P<0.05 compared to controls. (D) GIR of s.c. saline–infused controls (filled bars), OT-infused rats (50 nmol/d; open bars), and saline-infused PF controls (hatched bars). Values are mean ± SEM of 6 to 7 rats/group. *P<0.05.CC BY · PubMed Central
Figure 9 Summary of the metabolic effects of oxytocin. Upon chronic central (i.c.v.) or peripheral (s.c.) infusion into diet-induced obese rats, oxytocin (OT) increases triglyceride (TG) uptake, lipolysis, and fatty acid β-oxidation in adipose tissue. OT activates stearoyl-Coenzyme A desaturase 1 (Scd1) to produce the endocannabinoid oleoylethanolamide (OEA), a known ligand of PPAR-alpha. The action of OT on fatty acid β-oxidation is thus exerted by direct activation of PPAR-alpha target genes via the production of OEA. Red arrows indicate the direction (up or down) of regulation. Abbreviations: ACOX (acyl-CoA oxidase 1), ACC (acetyl-coenzyme A carboxylase alpha), ATGL (patatin-like phospholipase domain containing 2), DG (diglycerides), DGAT1 (diacylglycerol O-acyltransferase homolog 1), FA (fatty acid), FAS (fatty acid synthase), GLUT4 (glucose transporter-4), HD (enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase), HSL (hormone-sensitive lipase), LPL (lipoprotein lipase), MCAD (medium chain acyl-CoA dehydrogenase), MG (monoglycerides), MGL (monoglyceride lipase), NOPE (N-oleoyl-phosphatidylethanolamine), OA (oleic acid), SA (stearic acid), PPAR-α (peroxisome proliferator-activator receptor-alpha).
Figure 9 Summary of the metabolic effects of oxytocin. Upon chronic central (i.c.v.) or peripheral (s.c.) infusion into diet-induced obese rats, oxytocin (OT) increases triglyceride (TG) uptake, lipolysis, and fatty acid β-oxidation in adipose tissue. OT activates stearoyl-Coenzyme A desaturase 1 (Scd1) to produce the endocannabinoid oleoylethanolamide (OEA), a known ligand of PPAR-alpha. The action of OT on fatty acid β-oxidation is thus exerted by direct activation of PPAR-alpha target genes via the production of OEA. Red arrows indicate the direction (up or down) of regulation. Abbreviations: ACOX (acyl-CoA oxidase 1), ACC (acetyl-coenzyme A carboxylase alpha), ATGL (patatin-like phospholipase domain containing 2), DG (diglycerides), DGAT1 (diacylglycerol O-acyltransferase homolog 1), FA (fatty acid), FAS (fatty acid synthase), GLUT4 (glucose transporter-4), HD (enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase), HSL (hormone-sensitive lipase), LPL (lipoprotein lipase), MCAD (medium chain acyl-CoA dehydrogenase), MG (monoglycerides), MGL (monoglyceride lipase), NOPE (N-oleoyl-phosphatidylethanolamine), OA (oleic acid), SA (stearic acid), PPAR-α (peroxisome proliferator-activator receptor-alpha).CC BY · PubMed Central

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Authors
Deblon, N., Veyrat-Durebex, C., Bourgoin, L., Caillon, A., Bussier, A.-L., Petrosino, S., Piscitelli, F., Legros, J.-J., Geenen, V., Foti, M., Wahli, W., Di Marzo, V., & Rohner-Jeanrenaud, F.
Affiliations
  • University of Geneva (CH)
  • Istituto di Chimica Biomolecolare (IT)
  • University of Liège (BE)
  • University of Lausanne (CH)
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-09-27
Volume
6
Issue
9
Pages
e25565
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0025565
PMC
PMC3181274
OpenAlex
W2161253360
Cited by
254
References
42
Citations by year
2026: 7 · 2025: 11 · 2024: 20 · 2023: 12 · 2022: 18 · 2021: 25 · 2020: 16 · 2019: 23 · 2018: 22 · 2017: 22 · 2016: 19 · 2015: 17 · 2014: 20 · 2013: 16 · 2012: 5
FWCI
6.22
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
  • IRIS (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • Open Repository and Bibliography (University of Liège) (submittedVersion, other-oa)
  • SERVAL (Université de Lausanne) (submittedVersion, other-oa)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
Funders
  • National Science Foundation (310030)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (120147, 128660, 135727, 31003A, 31003A-134919/1, 134919, 310000, 310030, 3100A0)
  • National Institutes of Health (DA009789)
  • National Institute on Drug Abuse (P01DA009789)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords
oxytocin, anti-obesity, diet-induced obesity, high-fat diet, adipose tissue lipolysis, fatty acid beta-oxidation, insulin resistance, impaired glucose tolerance, PPARα, stearoyl-CoA desaturase 1, oleoylethanolamide, type 2 diabetes
MeSH terms
Adipose Tissue, Animals, Body Weight, Diet, Dose-Response Relationship, Drug, Insulin Resistance, Male, Obesity, Oleic Acids, Oxytocin, Anti-Obesity Agents, PPAR alpha, Mice, Rats, Gene Knockout Techniques, Endocannabinoids

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