High serum oxytocin is associated with metabolic syndrome in older men – The MINOS study

https://doi.org/10.1016/j.diabres.2016.09.022Get rights and content

Highlights

  • We assessed the association between serum oxytocin (OT) and metabolic syndrome (MetS).

  • In older men, higher OT levels were associated with higher odds of MetS.

  • High serum OT was associated with MetS regardless of testosterone or vitamin D level.

  • The men with high OT and low osteocalcin levels had higher odds of MetS.

Abstract

Aim

Oxytocin regulates food intake, carbohydrate and lipid metabolism, and urinary sodium excretion. We assessed the association between serum oxytocin levels and presence of metabolic syndrome (MetS) in older men.

Methods

Cross-sectional study was performed in 540 volunteer men aged 50–85 yrs from the MINOS cohort. Oxytocin was measured in fasting serum by radioimmunoassay (Oxytocin RIA, Phoenix Pharmaceuticals). MetS was diagnosed using the harmonized definition.

Results

Serum oxytocin was higher in 166 men with MetS vs. controls (p < 0.005). After adjustment for confounders including leptin, higher oxytocin was associated with higher odds of MetS (OR = 1.38 per SD, 95%CI: 1.10–1.71, p < 0.005). Men with serum oxytocin >0.74 pg/mL (median) had higher odds of MetS vs. men with oxytocin ⩽0.74 pg/mL (OR = 2.06, 95%CI: 1.33–3.18, p < 0.005). Higher oxytocin levels and low testosterone levels (total or free) were significantly associated with higher odds of MetS jointly and independently of each other. Men having oxytocin >0.74 pg/mL and total testosterone <300 ng/dL (<10.4 nmol/L) had higher odds of MetS vs. men without these characteristics (OR = 3.95, 95%CI: 1.65–9.46, p < 0.005). Men having 25-hydroxycholecalciferol levels <30 ng/mL and oxytocin >0.74 pg/mL had higher odds of MetS vs. men without these characteristics (OR = 2.86, 95%CI: 1.47–5.58, p < 0.01). Men having oxytocin >0.74 pg/mL and osteocalcin levels <14.6 ng/mL (lowest quartile) had higher odds of MetS vs. men without these characteristics (OR = 4.12, 95%CI: 2.07–8.20, p < 0.001).

Conclusion

In older men, higher serum oxytocin levels are associated with higher odds of MetS regardless of potential confounders.

Introduction

Oxytocin (OT) is a nonapeptide synthesized by supraoptic and paraventricular hypothalamic nuclei and secreted by the posterior lobe of the pituitary gland. It stimulates milk ejection and uterine contractility, regulates responses to stressors and modulates social interactions [1].

OT regulates caloric intake and body weight. Exogenous OT reduces caloric intake in humans [2]. In monkeys, chronic OT administration inhibits food intake and produces weight loss [3]. OT deficient mice and OT receptor-deficient mice develop obesity [4]. By contrast, data on the serum OT levels in obese individuals and those concerning the effect of food intake on serum OT levels are discordant [5], [6].

OT regulates the metabolism of carbohydrates and lipids. In healthy men OT administered intravenously increased serum levels of glucagon and glucose which was followed by an increase in insulin concentration [7]. This effect may be mediated by the OT receptor present on the A- and B-cells of pancreatic islets [8]. Conversely, administration of insulin increased serum OT level [9]. Combined exposure to insulin and glucose can elicit OT release via their effect on the insulin receptor and glucose transporters (GLUT3, GLUT4) localized on the magnocellular neurons of the supraoptic nucleus [10].

Regulation of lipid metabolism by OT was studied in animals. In lactating buffaloes OT increased serum glucose, triglycerides and cholesterol, and lowered HDL-cholesterol [11]. Conversely, oleoylethanolamide (OEA), synthesized in the small intestine after fat ingestion, stimulated OT synthesis in hypothalamus and reduced food intake [12], [13]. Moreover, OT stimulated beta-oxidation of fatty acids and increased energy expenditure [3].

Some studies suggested that OT regulates vascular tone and natriuresis [14]. Conversely, hypertonic volume expansion induced OT secretion [15]. Thus, OT may also contribute to the regulation of body fluid volume and of blood pressure.

Thus, OT seems to be involved in biological phenomena belonging to the metabolic syndrome (MetS). In addition, OT interacts with secretion and signaling of leptin which is involved in the regulation of energy metabolism [16]. Therefore, our aim was to assess the association between serum OT levels and MetS in older men accounting for other factors associated with MetS and supposed to influence the investigated relationship (e.g. sex steroids, vitamin D, lifestyle factors).

Section snippets

The MINOS cohort

The MINOS study is a prospective single center cohort study of osteoporosis that included men aged 50–85 years [17]. It is a collaborative project involving INSERM and Société de Secours Minière de Bourgogne (SSMB), a large local health insurance company, covering mineworkers and their families living in Greater Montceau-les-Mines (≈35,000 inhabitants). The study was accepted by the ethics committee and performed according to the Declaration of Helsinki as revised in 1983. The cohort was

Oxytocin, body fat and MetS components

The characteristics of the 540 men were as follows: average age 65 ± 7 years, average weight 80 ± 13 kg. Seventy men (13%) were current smokers, 79 men (16%) self-reported ischemic heart disease. Men who had higher OT levels were heavier (Table 1). They had higher prevalence of hypertension, diabetes mellitus and MetS as well as higher serum leptin levels.

In the multivariate models, weight, BMI, total fat and fraction, central and appendicular fat, and waist circumference increased across the OT

Discussion

In this cohort of older men, higher OT levels were associated with higher odds of MetS. The association remained significant after adjustment for confounders. High OT levels were associated with MetS independently of the levels of testosterone or 25OHD. Moreover, the men with high OT and low OC levels had higher odds of MetS.

OT inhibits food intake, increases energy expenditure and produces weight loss [2], [3]. OT-deficient and OT receptor-deficient mice develop obesity [4]. On the one hand,

Funding

This study was supported by a grant from INSERM/Merck Sharp & Dohme Chibret, France and by “Programme Hospitalier de Recherche Clinique InterRégional – Interrégion Sudméditerrannée – 2011” of the French Ministry of Health.

Clinical Trials.gov identifier: NCT01192893.

Author contribution

PS researched data, was responsible for the MINOS study over its entire duration, made most of the statistical analyses and wrote the manuscript. EZA performed the measurements of oxytocin and leptin, as well as contributed to the data interpretation and to the discussion. AV was responsible for the measurements of biological parameters of the metabolic syndrome. PPF performed the measurements of oxytocin and leptin, as well as contributed to the data interpretation and the discussion. EF

Conflict of interest

All the authors declare that they have no conflict of interest as concerns this manuscript.

References (51)

  • D. Cai et al.

    A new horizon: oxytocin as a novel therapeutic option for obesity and diabetes

    Drug Discov Today Dis Mech

    (2013)
  • V. Ott et al.

    Oxytocin reduces reward-driven food intake in humans

    Diabetes

    (2013)
  • J.E. Blevins et al.

    Chronic oxytocin administration inhibits food intake, increases energy expenditure, and produces weight loss in fructose-fed obese rhesus monkeys

    Am J Physiol Regul Integr Comp Physiol

    (2015)
  • C. Camerino

    Low sympathetic tone and obese phenotype in oxytocin-deficient mice

    Obesity (Silver Spring)

    (2009)
  • J.G. Verbalis et al.

    Oxytocin secretion in response to cholecystokinin and food: differentiation of nausea from satiety

    Science

    (1986)
  • W. Qian et al.

    Decreased circulating levels of oxytocin in obesity and newly diagnosed type 2 diabetic patients

    J Clin Endocrinol Metab

    (2014)
  • G. Paolisso et al.

    Effects of oxytocin upon the endocrine pancreas secretion and glucose turnover in normal man

    Acta Endocrinol (Copenh)

    (1990)
  • B.M. Fisher et al.

    Plasma oxytocin, arginine vasopressin and atrial natriuretic peptide responses to insulin-induced hypoglycaemia in man

    Clin Endocrinol (Oxf)

    (1987)
  • Z. Song et al.

    Supraoptic oxytocin and vasopressin neurons function as glucose and metabolic sensors

    Am J Physiol Regul Integr Comp Physiol

    (2014)
  • Z. Iqbal et al.

    Effect of oxytocin on serum biochemistry, liver enzymes, and metabolic hormones in lactating Nili Ravi buffaloes

    Trop Anim Health Prod

    (2015)
  • F. Rodríguez de Fonseca et al.

    An anorexic lipid mediator regulated by feeding

    Nature

    (2001)
  • M.A. Haanwinckel et al.

    Oxytocin mediates atrial natriuretic peptide release and natriuresis after volume expansion in the rat

    Proc Natl Acad Sci USA

    (1995)
  • L.O. Margatho et al.

    Oxytocin in the central amygdaloid nucleus modulates the neuroendocrine responses induced by hypertonic volume expansion in the rat

    J Neuroendocrinol

    (2013)
  • J.E. Blevins et al.

    Evidence that paraventricular nucleus oxytocin neurons link hypothalamic leptin action to caudal brain stem nuclei controlling meal size

    Am J Physiol Regul Integr Comp Physiol

    (2004)
  • V. Breuil et al.

    Oxytocin and bone status in men: analysis of the MINOS cohort

    Osteoporos Int

    (2015)
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