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Leptin and Amylin Act in an Additive Manner to Activate Overlapping Signaling Pathways in Peripheral Tissues in Vitro and Ex Vivo Studies in Humans

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Leptin and Amylin Act in an Additive Manner to Activate Overlapping Signaling Pathways in Peripheral Tissues in Vitro and Ex Vivo Studies in Humans Pathophysiology/Complications ORIGINAL ARTICLE Leptin and Amylin Act in an Additive Manner to Activate Overlapping Signaling Pathways in Peripheral Tissues In vitro and ex vivo studies in humans 1 1 HYUN-SEUK MOON, PHD FLORENCIA ZIEMKE, MD cose-dependent manner (5). Moreover, it 1 2 JOHN P. CHAMBERLAND, BS BENJAMIN SCHNEIDER, MD has been proposed that treatment with a 1 1,3 KALLIOPE N. DIAKOPOULOS, BS CHRISTOS S. MANTZOROS, MD 1 combination of amylin and leptin may be CHRISTINA G. FIORENZA, BS more effective than leptin or amylin alone for obesity treatment in both animals (2) and humans (5). OBJECTIVE — Amylin interacts with leptin to alter metabolism. We evaluated, for the first Comprehensive pharmacological time, amylin- and/or leptin-activated signaling pathways in human peripheral tissues (hPTs). studies demonstrated that concurrent amylin and leptin infusion synergistically RESEARCH DESIGN AND METHODS — Leptin and amylin signaling studies were reduce body weight and adiposity in diet- performed in vitro in human primary adipocytes (hPAs) and human peripheral blood mononu- clear cells (hPBMCs) and ex vivo in human adipose tissue (hAT) from male versus female induced obesity in rats (6). It has also subjects, obese versus lean subjects, and subjects with subcutaneous versus omental adipose been demonstrated that acute amylin in- tissue. fusion amplifies central leptin signaling, and with sustained treatment amylin and RESULTS — The long form of leptin receptor was expressed in human tissues and cells leptin elicit synergistic weight and fat loss studied in ex vivo and in vitro, respectively. Leptin and amylin alone and in combination activate (6). Amylin-treated rats demonstrate a signal transducer and activator of transcription 3 (STAT3), AMP-activated protein kinase, Akt, trend for a greater number of phosphory- and extracellular signal-regulated kinase signaling pathways in hAT ex vivo and hPAs and lated (p)-signal transducer and activator hPBMCs in vitro; all phosphorylation events were saturable at leptin and amylin concentrations of ϳ50 and ϳ20 ng/ml, respectively. The effects of leptin and amylin on STAT3 phosphorylation of transcription (STAT) 3–positive cells in hPAs and hPBMCs in vitro were totally abolished under endoplasmic reticulum stress and/ within the arcuate nucleus than vehicle- or in the presence of a STAT3 inhibitor. Results similar to those in the in vitro studies were treated controls, an effect similar to that of observed in hAT studied ex vivo. leptin, whereas rats treated with both amylin and leptin have significantly more CONCLUSIONS — Leptin and amylin activate overlapping intracellular signaling pathways p-STAT3–positive cells than vehicle-, in humans and have additive, but not synergistic, effects in signaling pathways studied in hPTs amylin-, or leptin-treated rats (7). Fur- in vitro and ex vivo. thermore, this study also demonstrated that leptin receptor mRNA was signifi- Diabetes Care 34:132–138, 2011 cantly increased by amylin/leptin coinfu- sion both centrally and peripherally, i.e., eptin is an adipocyte-secreted hor- body weight is reduced (3). Moreover, in white adipose tissue and liver (7). mone that plays a major role in en- leptin improves insulin resistance in lep- Moreover, it has been shown that periph- L ergy homeostasis and weight balance tin-deficient lipoatrophic mice and hu- eral leptin injection in rodents increases (1). Leptin not only activates central ner- mans with the metabolic syndrome and STAT3 and mitogen-activated protein ki- vous system networks that suppress ap- insulin resistance (3). Amylin is a 37- nase (MAPK) phosphorylation in liver petite (1) but also acts in the periphery to amino acid peptide hormone that is cose- and adipose tissue (8). No previous study alter immune function and metabolism creted with insulin from pancreatic ␤ has evaluated leptin and amylin signaling (2). Leptin administration to leptin- -cells (4). The physiological effects of in human peripheral tissues (hPTs) nor deficient (ob/ob) mice has been shown to amylin receptor agonism include de- investigated how amylin interacts with reduce food intake and body mass and creased food intake (4) and reduction of leptin to alter signaling in hPTs. improve insulin resistance even before postprandial glucagon release in a glu- We performed ex vivo and in vitro ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● signaling studies to clarify the role of lep- From the 1Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, tin and amylin in activating signaling Harvard Medical School, Boston, Massachusetts; the 2Division of Minimally Invasive Surgery, Beth Israel pathways in hPTs as well as their potential Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and the 3Section of Endo- interactions. We first investigated in vitro crinology, Boston VA Healthcare System, Harvard Medical School, Boston, Massachusetts. leptin and amylin signaling in human pri- Corresponding author: Christos S. Mantzoros, [email protected]. Received 19 March 2010 and accepted 18 September 2010. Published ahead of print at http://care. mary adipocytes (hPAs) and human pe- diabetesjournals.org on 24 September 2010. DOI: 10.2337/dc10-0518. ripheral blood mononuclear cells © 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly (hPBMCs), known cell targets of leptin ac- cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. tion. We then performed ex vivo leptin org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby and amylin signaling studies in human marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. adipose tissue (hAT) from subjects with 132 DIABETES CARE, VOLUME 34, NUMBER 1, JANUARY 2011 care.diabetesjournals.org Moon and Associates subcutaneous versus omental adipose tis- a 1-min annealing-elongation step at mented with 25 mmol/l HEPES, 2 mmol/l sue, male versus female subjects, and 60°C. The analysis of relative gene expres- L-glutamine, 100 ␮U/ml penicillin, 100 ⌬ ␮ ␮ obese versus lean subjects. sion was based on Ct values obtained g/ml streptomycin, and 2.5 g/ml am- from RT-PCR (9). photericin B. RESEARCH DESIGN AND METHODS — We used hAT from Ex vivo signaling study in hAT subjects undergoing laparoscopic adjust- The ex vivo culture was established ac- Endoplasmic reticulum stress able gastric banding, hernioplasty, lipo- cording to the method described by Kim induction suction, or abdominoplasty. The study et al. (8). In brief, 5–7 g of fresh subcuta- The induction of endoplasmic reticulum protocol was approved by the Institu- neous and/or omental hAT was placed stress was established according to the tional Review Board at the Beth Israel into Krebs-Ringer-HEPES buffer (20 method described by Hagiwara et al. (12). Deaconess Medical Center, and subjects mmol/l, pH 7.4) with 2.5% BSA and 200 In brief, to induce endoplasmic reticulum gave written informed consent to partici- nmol/l adenosine at 37°C in the operating stress, the cells were pretreated with TUN pate. All subjects were otherwise healthy, room and immediately taken to the labo- (3 ␮g/ml) and/or DTT (1 mmol/l) for 5 h had no evidence of immunological or en- ratory for further analysis. In the labora- and subsequently treated with leptin docrine disease based on physical exami- tory, the tissue samples were minced into and/or amylin. nation and routine blood tests, and had pieces of ϳ1 mm in diameter, and any no history of recent infection. The sub- nonadipose and nonmuscle tissue was re- jects’ age, vital signs, and BMI were re- moved by washing with fresh buffer. The Protein extraction corded. We collected tissue samples from samples were aliquoted and incubated at For total cell extracts, collected cells were obese (six men and six women aged 37°C either with or without amylin and suspended in a lysis buffer containing 20 31–54 years old with BMI 42–44 kg/m2) leptin. mmol/l Tris-HCl (pH 7.4), 150 mmol/l and lean (three men and four women aged NaCl, 5 mmol/l EDTA, 0.1 mmol/l phe- 22–32 years old with BMI 21–23 kg/m2) hPA culture nylmethylsulfonyl fluoride, 0.05% apro- subjects. The hPA culture was established accord- tinin, and 0.1% Igepal and then incubated ing to the method described by Ribet et al. for 30 min at 4°C. The suspension was Materials (10). In brief, subcutaneous and omental centrifuged for 25min at 14,240g, and the All primary and secondary antibodies hAT samples were obtained from lean supernatant was saved as the total extract. were purchased from Santa Cruz Biotech- (35–41 years old, BMI 22–25 kg/m2) and Next, the pellet was resuspended in a lysis nology (Santa Cruz, CA). Leptin human obese (34–48 years old, BMI 39–50 kg/ buffer containing 50 mmol/l HEPES- recombinants were purchased from m2) men and women, respectively. The NaOH (pH 7.8), 50 mmol/l KCl, 300 ProSpec-Tany TechnoGene (Rehovot, Is- hAT was then digested with PBS/ mmol/l NaCl, 0.1 mmol/l EDTA, 1 rael). Amylin human recombinants were collagenase solution (3 mg collagenase/g mmol/l DTT, 0.1 mmol/l phenylmethyl- purchased from Phoenix Pharmaceuticals tissue and 1 ml PBS/1 mg collagenase) ϩ sulfonyl fluoride, and 10% (v/v) glycerol. (Burlingame, CA). FBS and FCS were pro- 3.5% fatty acid–free BSA and then filtered The suspension was mixed for 30 min at vided by Gibco Life Technologies. BSA, using a filter bottle unit (sterile funnel 4°C and centrifuged for 15 min at 890g; ␣-minimal essential medium (␣-MEM), with double-layered gauze), and the solu- the supernatant was saved as the nuclear RPMI 1640, NaHCO3, HEPES, biotin, tion was centrifuged at 1200 rpm for 10 extract.
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