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Nava Chapnik Robert H. Smith Faculty of Agriculture, Fritz Haber Center for Molecular Dynamics, Food and Environment, Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel

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Yoni Genzer Robert H. Smith Faculty of Agriculture, Fritz Haber Center for Molecular Dynamics, Food and Environment, Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel

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Avraham Ben-Shimon Robert H. Smith Faculty of Agriculture, Fritz Haber Center for Molecular Dynamics, Food and Environment, Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel
Robert H. Smith Faculty of Agriculture, Fritz Haber Center for Molecular Dynamics, Food and Environment, Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel

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Masha Y Niv Robert H. Smith Faculty of Agriculture, Fritz Haber Center for Molecular Dynamics, Food and Environment, Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel
Robert H. Smith Faculty of Agriculture, Fritz Haber Center for Molecular Dynamics, Food and Environment, Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel

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Oren Froy Robert H. Smith Faculty of Agriculture, Fritz Haber Center for Molecular Dynamics, Food and Environment, Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel

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AMP-activated protein kinase (AMPK) is a regulator of energy balance at both the cellular and the whole-body levels. Direct activation of AMPK has been highlighted as a potential novel, and possibly safer, alternative to treat type II diabetes and obesity. In this study, we aimed to design and characterize novel peptides that mimic the αG region of the α2 AMPK catalytic domain to modulate its activity by inhibiting interactions between AMPK domains or other interacting proteins. The derived peptides were tested in vivo and in tissue culture. The computationally predicted structure of the free peptide with the addition of the myristoyl (Myr) or acetyl (Ac) moiety closely resembled the protein structure that it was designed to mimic. Myr-peptide and Ac-peptide activated AMPK in muscle cells and led to reduced adipose tissue weight, body weight, blood glucose levels, insulin levels, and insulin resistance index, as expected from AMPK activation. In addition, triglyceride, cholesterol, leptin, and adiponectin levels were also lower, suggesting increased adipose tissue breakdown, a result of AMPK activation. On the other hand, liver weight and liver lipid content increased due to fat retention. We could not find an elevated pAMPK:AMPK ratio in the liver in vivo or in hepatocytes ex vivo, suggesting that the peptide does not lead to AMPK activation in hepatocytes. The finding that an AMPK-derived peptide leads to the activation of AMPK in muscle cells and in adipose tissue and leads to reduced glucose levels in obese mice, but to fat accumulation in the liver, demonstrates the differential effect of AMPK modulation in various tissues.

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Nava Chapnik
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Gili Solomon
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Yoni Genzer
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Ruth Miskin Robert H. Smith Faculty of Agriculture, Department of Biological Chemistry, Food and Environment, Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot 76100, Israel

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Arieh Gertler
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Oren Froy
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Transgenic alpha murine urokinase-type plasminogen activator (αMUPA) mice are resistant to obesity and their locomotor activity is altered. As these mice have high leptin levels, our objective was to test whether leptin is responsible for these characteristics. αMUPA, their genetic background control (FVB/N), and C57BL mice were injected s.c. every other day with 20 mg/kg pegylated superactive mouse leptin antagonist (PEG-SMLA) for 6 weeks. We tested the effect of PEG-SMLA on body weight, locomotion, and bone health. The antagonist led to a rapid increase in body weight and subsequent insulin resistance in all treated mice. Food intake of PEG-SMLA-injected animals increased during the initial period of the experiment but then declined to a similar level to that of the control animals. Interestingly, αMUPA mice were found to have reduced bone volume (BV) than FVB/N mice, although PEG-SMLA increased bone mass in both strains. In addition, PEG-SMLA led to disrupted locomotor activity and increased corticosterone levels in C57BL but decreased levels in αMUPA or FVB/N mice. These results suggest that leptin is responsible for the lean phenotype and reduced BV in αMUPA mice; leptin affects corticosterone levels in mice in a strain-specific manner; and leptin alters locomotor activity, a behavior determined by the central circadian clock.

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