Recent studies suggest that proinsulin-connecting peptide (C-peptide) may exhibit characteristics of a hormone and show physiological functions in various tissues. This study was aimed to determine whether C-peptide could be involved in the regulation of lipolysis, adiponectin release, and function of mesenchymal stem cells (MSCs) in adipose tissue. Human subcutaneous adipose tissue was cultured in the presence of C-peptide. The level of lipolysis was determined by glycerol measurement in the conditioned media. Effect of C-peptide on adiponectin secretion was evaluated in differentiated adipocytes. The adipogenic and osteogenic abilities of adipose MSCs were evaluated using oil red and alizarin red staining, respectively. The tetrazolium bromide test was conducted for evaluating the effect of C-peptide on MSCs proliferation. C-peptide induced a significant decrease in basal lipolysis at concentrations of 8 and 16 nM (p < 0.05). It had no significant effects on isoproterenol-stimulated lipolysis, adiponectin secretion, and adipogenic or osteogenic differentiation of MSCs. At a concentration of 4 nM, this peptide significantly increased the proliferative capability of MSCs (p < 0.05). These results suggest that C-peptide has some physiological effects in human subcutaneous adipose tissue and contributes to the regulation of basal lipolysis and pool of MSCs.
Adamczak M , Wiecek A : The adipose tissue as an endocrine organ. Semin. Nephrol. 33, 2–13 (2013)
Aguena M , Dalto Fanganiello R , Tissiani LAL , Ishiy FAA , Atique R , Alonso N , Passos-Bueno MR : Optimization of parameters for a more efficient use of adipose-derived stem cells in regenerative medicine therapies. Stem Cells Int. 2012, 303610 (2012)
Alford AI , Reddy AB , Goldstein SA , Murthy P , Tayim R , Sharma G : Two molecular weight species of thrombospondin-2 are present in bone and differentially modulated in fractured and nonfractured tibiae in a murine model of bone healing. Calcif. Tissue Int. 90, 420–428 (2012)
Arca M , Pigna G , Favoccia C : Mechanisms of diabetic dyslipidemia: relevance for atherogenesis. Curr. Vasc. Pharmacol. 10, 684–686 (2012)
Arner P : Differences in lipolysis between human subcutaneous and omental adipose tissues. Ann. Med. 27, 435–438 (1995)
Brandenburg D : History and diagnostic significance of C-peptide. Exp. Diabetes Res. 2008, 576862 (2008)
Cianfarani F , Toietta G , Di Rocco G , Cesareo E , Zambruno G , Odorisio T : Diabetes impairs adipose tissue-derived stem cell function and efficiency in promoting wound healing. Wound Repair Regen. 21, 545–553 (2013)
Cifarelli V , Geng X , Styche A , Lakomy M , Trucco M , Luppi P : C-peptide reduces high glucose-induced apoptosis of endothelial cells and decreases NAD(P)H-oxidase reactive oxygen species generation. Diabetologia 54, 2702–2712 (2011)
Coelho M , Oliveira T , Fernandes R : Biochemistry of adipose tissue: an endocrine organ. Arch. Med. Sci. 9, 191–200 (2013)
Ducharme NA , Bickel PE : Lipid droplets in lipogenesis and lipolysis. Endocrinology 149, 942–949 (2008)
Eiras S , Teijeira-Fernández E , Shamagian LG , Fernandez AL , Vazquez-Boquete A , Gonzalez-Juanatey JR : Extension of coronary artery disease is associated with increased IL-6 and decreased adiponectin gene expression in epicardial adipose tissue. Cytokine 43, 174–180 (2008)
Fadini GP , Albiero M , Vigili de Kreutzenberg S , Boscaro E , Cappellari R , Marescotti M , Poncina N , Agostini C , Avogaro A : Diabetes impairs stem cell and proangiogenic cell mobilization in humans. Diabetes Care 36, 943–949 (2013)
Fakhry M , Hamade E , Badran B , Buchet R , Magne D : Molecular mechanisms of mesenchymal stem cell differentiation towards osteoblasts. World J. Stem Cells 5, 136–148 (2013)
Farmer SR : Transcriptional control of adipocyte formation. Cell Metab. 4, 263–273 (2006)
Garcia-Serrano S , Gutiérrez-Repiso C , Gonzalo M , Garcia-Arnes J , Valdes S , Soriguer F , Perez-Valero V , Alaminos-Castillo MA , Francisco Cobos-Bravo J , Moreno-Ruiz FJ , Rodriguez-Cañete A , Rodríguez-Pacheco F , Garcia-Escobar E , García-Fuentes E : C-peptide modifies leptin and visfatin secretion in human adipose tissue. Obesity 23, 1607–1615 (2015)
Ghorbani A , Hadjzadeh MR , Rajaei Z , Zendehbad SB : Effects of fenugreek seeds on adipogenesis and lipolysis in normal and diabetic rat. Pak. J. Biol. Sci. 17, 523–528 (2014)
Ghorbani A , Jalali SA , Varedi M : Isolation of adipose tissue mesenchymal stem cells without tissue destruction: a non-enzymatic method. Tissue Cell 46, 54–58 (2014)
Ghorbani A , Naderi-Meshkinb H : The endocrine regulation of stem cells: physiological importance and pharmacological potentials for cell-based therapy. Curr. Stem Cell Res. Ther. 11, 19–34 (2016)
Ghorbani A , Omrani GH , Hadjzadeh MR , Varedi M : Effects of rat C-peptide-II on lipolysis and glucose consumption in cultured rat adipose tissue. Exp. Clin. Endocrinol. Diabetes 119, 343–347 (2011)
Ghorbani A , Omrani GH , Hadjzadeh MR , Varedi M : Proinsulin C-peptide inhibits lipolysis in diabetic rat adipose tissue through phosphodiestrase-3B enzyme. Horm. Metab. Res. 45, 221–225 (2013)
Ghorbani A , Shafiee-Nick R : Pathological consequences of C-peptide deficiency in insulin-dependent diabetes mellitus. World J. Diabetes 6, 145–150 (2015)
Ghorbani A , Varedi M , Hadjzadeh MR , Omrani GH : Type-1 diabetes induces depot-specific alterations in adipocyte diameter and mass of adipose tissues in the rat. Exp. Clin. Endocrinol. Diabetes 118, 442–448 (2010)
Grunberger G , Qiang X , Li Z , Sbrissa D , Shisheva A , Sima AA : Molecular basis for the insulinomimetic effects of C-peptide. Diabetologia 44, 1247–1257 (2001)
Hajer GR , van Haeften TW , Visseren FL : Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur. Heart J. 29, 2959–2971 (2008)
Hansen A , Johansson BL , Wahren J , von Bibra H : C-peptide exerts beneficial effects on myocardial blood flow and function in patients with type 1 diabetes. Diabetes 51, 3077–3082 (2002)
Hills CE , Brunskill NJ : C-Peptide and its intracellular signaling. Rev. Diabet. Stud. 6, 138–147 (2009)
Jo J , Gavrilova O , Pack S , Jou W , Mullen S , Sumner AE , Cushman SW , Periwal V : Hypertrophy and/or hyperplasia: dynamics of adipose tissue growth. PLoS Comput. Biol. 5, e1000324 (2009)
Johansson BL , Borg K , Fernqvist-Forbes E , Odergren T , Remahl S , Wahren J : C-peptide improves autonomic nerve function in IDDM patients. Diabetologia 39, 687–695 (1996)
Johansson BL , Sundell J , Ekberg K , Jonsson C , Seppänen M , Raitakari O , Luotolahti M , Nuutila P , Wahren J , Knuuti J : C-peptide improves adenosine-induced myocardial vasodilation in type 1 diabetes patients. Am. J. Physiol. Endocrinol. Metab. 286, E14–E19 (2004)
Jumabay M , Moon JH , Yeerna H , Boström KI : Effect of diabetes mellitus on adipocyte-derived stem cells in rat. J. Cell Physiol. 230, 2821–2828 (2015)
Kersten S : Mechanisms of nutritional and hormonal regulation of lipogenesis. EMBO Rep. 2, 282–286 (2001)
Klaus S : Adipose tissue as a regulator of energy balance. Curr. Drug Targets 5, 241–250 (2004)
Kunt T , Schneider S , Pfutzner A , Goitum K , Engelbach M , Schauf B , Beyer J , Forst T : The effect of human proinsulin C-peptide on erythrocyte deformability in patients with Type I diabetes mellitus. Diabetologia 42, 465–471 (1999)
Lafontan M : Adipose tissue and adipocyte dysregulation. Diabetes Metab. 40, 16–28 (2014)
Lafontan M , Langin D : Lipolysis and lipid mobilization in human adipose tissue. Prog. Lipid Res. 48, 275–297 (2009)
Lefterova MI , Lazar MA : New developments in adipogenesis. Trends Endocrinol. Metab. 20, 107–114 (2009)
Minteer DM , Young MT , Lin YC , Over PJ , Rubin JP , Gerlach JC , Marra KG : Analysis of type II diabetes mellitus adipose-derived stem cells for tissue engineering applications. J. Tissue Eng. 6, 2041731415579215 (2015)
Montague CT , Prins JB , Sanders L , Digby JE , O’Rahilly S : Depot- and sex-specific differences in human leptin mRNA expression implications for the control of regional fat distribution. Diabetes 46, 342–347 (1997)
Motoshima H , Wu X , Sinha MK , Hardy VE , Rosato EL , Barbot DJ , Rosato FE , Goldstein BJ : Differential regulation of adiponectin secretion from cultured human omental and subcutaneous adipocytes: effects of insulin and rosiglitazone. J. Clin. Endocrinol. Metab. 87, 5662–5667 (2002)
Nerlov C : The C/EBP family of transcription factors: a paradigm for interaction between gene expression and proliferation control. Trends Cell Biol. 17, 318–324 (2007)
Nordquist L , Moe E , Sjoquist M : The C-peptide fragment EVARQ reduces glomerular hyperfiltration in streptozotocin-induced diabetic rats. Diabetes Metab. Res. Rev. 23, 400–405 (2007)
Ong WK , Sugii S : Adipose-derived stem cells: fatty potentials for therapy. Int. J. Biochem. Cell Biol. 45, 1083–1086 (2013)
Raghupathy P : Diabetic ketoacidosis in children and adolescents. Indian J. Endocrinol. Metab. 19(Suppl . 1), S55–S57 (2015)
Richelsen B , Pedersen SB , Moller-Pedersen T , Bk JF : Regional differences in triglyceride breakdown in human adipose tissue: effects of catecholamines, insulin, and prostaglandin E2. Metabolism 40, 990–996 (1991)
Rosen ED , Spiegelman BM : Molecular regulation of adipogenesis. Annu. Rev. Cell Dev. Biol. 16, 145–171 (2000)
Sato Y , Oshida Y , Han YQ , Morishita Y , Li L , Ekberg K , Jörnvall H , Wahren J : C-peptide fragments stimulate glucose utilization in diabetic rats. Cell. Mol. Life Sci. 61, 727–732 (2004)
Spalding KL , Arner E , Westermark PO , Bernard S , Buchholz BA , Bergmann O , Blomqvist L , Hoffstedt J , Näslund E , Britton T , Concha H , Hassan M , Rydén M , Frisén J , Arner P : Dynamics of fat cell turnover in humans. Nature 453, 783–787 (2008)
Stolic M , Russel A , Hutley L , Fielding G , Hay J , MacDonald G , Whitehead J , Prins J : Glucose uptake and insulin action in human adipose tissue influence of BMI, anatomical depot and body fat distribution. Int. J. Obes. Relat. Metab. Disord. 26, 17–23 (2002)
Turer AT , Scherer PE : Adiponectin: mechanistic insights and clinical implications. Diabetologia 55, 2319–2326 (2012)
Van Harmelen V , Lonnqvist F , Thorne A , Wennlund A , Large V , Reynisdottir S , Arner P : Noradrenaline-induced lipolysis in isolated mesenteric, omental and subcutaneous adipocytes from obese subjects. Int. J. Obes. Relat. Metab. Disord. 21, 972–979 (1997)
Virtanen KA , Lonnroth P , Parkkola R , Peltoniemi P , Asola M , Viljanen T , Tolvanen T , Knuuti J , Rönnemaa T , Huupponen R , Nuutila P : Glucose uptake and perfusion in subcutaneous and visceral adipose tissue during insulin stimulation in nonobese and obese humans. J. Clin. Endocrinol. Metab. 87, 3902–3910 (2002)
Wahren J , Foyt H , Daniels M , Arezzo JC : Long-acting c-peptide and neuropathy in type 1 diabetes: a 12-month clinical trial. Diabetes Care 39, 596–602 (2016)
Wahren J , Larsson C : C-peptide: new findings and therapeutic possibilities. Diabetes Res. Clin. Pract. 107, 309–319 (2015)
Yamauchi T , Kadowaki T : Physiological and pathophysiological roles of adiponectin and adiponectin receptors in the integrated regulation of metabolic and cardiovascular diseases. Int. J. Obes. (Lond.) 32, S13–S18 (2008)
Zierath GR , Livingston JN , Thorne A , Bolinder J , Reynisdottir S , Lönnqvist F , Arner P : Regional difference in insulin inhibition of non-esterified fatty acid release from human adipocytes: relation to insulin receptor phosphorylation and intracellular signalling through the insulinreceptor substrate-1 pathway. Diabetologia 41, 1343–1354 (1998)