Elsevier

Peptides

Volume 61, November 2014, Pages 75-82
Peptides

Obese patients have higher circulating protein levels of dipeptidyl peptidase IV

https://doi.org/10.1016/j.peptides.2014.09.006Get rights and content

Highlights

  • Dipeptidyl peptidase IV (DPPIV) is involved in various homeostatic processes.

  • Obese have higher DPPIV protein levels compared to normal weight controls.

  • DPPIV activity was similar while concentration/activity ratio was higher in obese.

  • Plasma pancreatic polypeptide negatively correlates with body mass index.

  • The increased ratio might contribute to reduced anorexigenic signaling.

Abstract

Dipeptidyl peptidase IV (DPPIV) is a protease with broad distribution involved in various homeostatic processes such as immune defense, psychoneuroendocrine functions and nutrition. While DPPIV protein levels were investigated in patients with hyporectic disorders, less is known under conditions of obesity. Therefore, we investigated DPPIV across a broad range of body mass index (BMI). Blood samples from hospitalized patients with normal weight (BMI 18.5–25 kg/m2), anorexia nervosa (BMI <17.5 kg/m2) and obesity (BMI 30–40, 40–50 and >50 kg/m2, n = 15/group) were tested cross-sectionally and DPPIV concentration and total enzyme activity and the DPPIV targets, pancreatic polypeptide (PP) and glucagon-like peptide (GLP-1) were measured. DPPIV protein expression was detected in human plasma indicated by a strong band at the expected size of 110 kDa and another major band at 50 kDa, likely representing a fragment comprised of two heavy chains. Obese patients had higher DPPIV protein levels compared to normal weight and anorexics (+50%, p < 0.05) resulting in a positive correlation with BMI (r = 0.34, p = 0.004). DPPIV serum activity was similar in all groups (p > 0.05), while the concentration/activity ratio was higher in obese patients (p < 0.05). Plasma PP levels were highest in anorexic patients (∼2-fold increase compared to other groups, p < 0.05), whereas GLP-1 did not differ among groups (p < 0.05). Taken together, circulating DPPIV protein levels depend on body weight with increased levels in obese resulting in an increased concentration/activity ratio. Since DPPIV deactivates food intake-inhibitory hormones like PP, an increased DPPIV concentration/activity ratio might contribute to reduced food intake-inhibitory signaling under conditions of obesity.

Introduction

The prevalence of obesity is expanding worldwide in industrialized and also developing countries and therefore the term “globesity” was created (homepage world health organization). Obesity is associated with several diseases such as type 2 diabetes mellitus, dyslipidemia and arteriosclerosis (leading to an increased risk for cardiovascular diseases) [10], sleep apnea [20], degenerative joint diseases [2], mental disorders [21], [24] and certain forms of cancer including hepatocellular, colorectal, pancreatic [6] and breast cancer [4]. Therefore, obesity is a major medical problem for the patient as well as a socioeconomic burden for the society [27]. It has been known for a long time that already a modest (5–10%) weight loss leads to an improvement of the patients’ metabolic situation [9], [30]. However, drug treatment options are very limited so far [14]. Therefore, a better understanding of the mechanisms regulating hunger and satiety is necessary.

Hunger and satiety are regulated by a multitude of peptide and protein hormones that exert their food intake-modulatory actions in the brain but most of them are predominantly produced in the gastrointestinal tract [26]. While ghrelin is the only peripherally produced and centrally acting hormone that stimulates food intake, a number of gastrointestinal hormones are involved in the reduction of food intake, including cholecystokinin, oxyntomodulin, peptide YY (PYY), pancreatic polypeptide (PP) and glucagon-like peptide 1 (GLP-1) [26]. Interestingly, several of these hormones, namely PYY, PP and GLP-1 are target to dipeptidyl peptidase IV (DPPIV) resulting in cleavage and inactivation of PP and GLP-1, while a feeding-modulatory effect has been described for PYY due to different receptor binding [11].

DPPIV (also known as CD26) is a serine exopeptidase that is widely expressed in the body and exerts pleiotropic functions with an involvement in immune functions, inflammation, glucose homeostasis, regulation of hunger and satiety and psychomodulation [11]. Especially the involvement in glucose control is of clinical interest since several DPPIV inhibitors such as sitagliptin, saxagliptin, linagliptin and alogliptin are on the market as antidiabetic drugs [8]. Besides the beneficial effects on glucose homeostasis, some of these compounds also – although modestly – reduce body weight [5], a favorable effect in obesity-associated diabetes mellitus. Contrasting with the wide clinical use of DPPIV inhibitors, the knowledge on the regulation of DPPIV under conditions of chronically altered body weight, especially obesity is limited. Moreover, mostly DPPIV enzyme activity is assessed, while the protein concentration is not described. One study reported lowered DPPIV enzyme activity in serum of patients with anorexia nervosa compared to normal weight controls [29], whereas another study described the opposite result with an elevation of serum DPPIV activity levels in anorexic compared to healthy subjects [13]. In healthy normal weight subjects, plasma DPPIV enzyme activity was positively correlated with body mass index (BMI) [17], a finding that was also described in obese children [19]. This may be due to higher expression of DPPIV in adipose tissue as recently hypothesized [22].

Therefore, the aim of this study was to investigate circulating DPPIV protein concentrations as well as total enzyme activity across a broad range of BMI (9–85 kg/m2). For this reason, the patient population was divided into groups according to the BMI: anorexia nervosa (BMI <17.5 kg/m2), normal weight (BMI 18.5–25 kg/m2) and three groups of obesity (BMI 30–40, 40–50 and >50 kg/m2). To investigate the possible effect of an altered DPPIV concentration, we also measured circulating levels of PP and GLP-1, two major molecules subject to degradation by DPPIV.

Section snippets

Subjects

All patients were hospitalized in the Division of Psychosomatic Medicine at Charité-Universitätsmedizin Berlin and gave written informed consent. Blood collection was performed on day 2 or 3 after hospital admission before the onset of changes due to dietary treatment to increase or reduce body weight, respectively. All parameters were assessed on the same morning. The protocol was approved by the local ethics committee for human research (ethics committee Campus Charité Mitte, protocol number

Circulating DPPIV concentration is dependent on body mass index

The Western blot stained for DPPIV showed two prominent bands: one at the expected size of 110 kDa indicating full length DPPIV protein and the other one at 50 kDa which is likely to represent a fragment comprised of two heavy chains of DPPIV (Fig. 1).

Next, we investigated whether the expression of DPPIV would differ dependent on BMI. The study sample was separated into five BMI groups: anorexia nervosa (BMI < 17.5 kg/m2), normal weight (BMI 18.5–25 kg/m2) and three obese groups (BMI 30–40, 40–50 and

Discussion

In the present study we showed that DPPIV protein concentration is correlated with body mass index with an increased concentration in obese and the lowest concentration in patients with anorexia nervosa. The increased DPPIV concentration is not due to an overall alteration of protein expression as circulating total protein levels were not altered in the five BMI groups of patients. In addition, DPPIV protein concentrations were corrected for serum albumin levels. The Western blot detected two

Acknowledgements

This work was supported by the German Research Foundation STE 1765/3-1 (A.S.), Charité University Funding UFF 89-441-176 (A.S.) and the Sonnenfeld Foundation Berlin (P.K. and A.S.). We thank Reinhard Lommel and Petra Moschansky for their excellent technical support, Karin Johansson and Christina Hentzschel for help with organization and execution of anthropometric measurements and Friederice Schröder and Florian Bruckbauer for maintaining the database.

References (31)

  • E.E. Calle et al.

    Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults

    N Engl J Med

    (2003)
  • S.L. Conarello et al.

    Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance

    Proc Natl Acad Sci U S A

    (2003)
  • D.L. Eckerle Mize et al.

    The place of GLP-1-based therapy in diabetes management: differences between DPP-4 inhibitors and GLP-1 receptor agonists

    Curr Diab Rep

    (2013)
  • D.J. Goldstein

    Beneficial health effects of modest weight loss

    Int J Obes Relat Metab Disord

    (1992)
  • A.L. Hevener et al.

    The 2009 stock conference report: inflammation, obesity and metabolic disease

    Obes Rev

    (2010)
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