{'fraction_non_alphanumeric': 0.028840494408475574, 'fraction_numerical': 0.01942319011183049, 'mean_word_length': 5.367041198501872, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Peptide hormone isoforms: N‐terminally branched PYY3–36 isoforms give improved lipid and fat‐cell metabolism in diet‐induced obese mice

The prevalence of obesity is increasing with an alarming rate worldwide and there is a need for efficacious satiety drugs. PYY3–36 has been shown to play a role in hypothalamic appetite regulation and novel analogs targeting the Y2 receptor have potential as drugs for the treatment of obesity. We have designed a series of novel PYY3–36 isoforms, by first adding the dipeptide Ile–Lys N‐terminal to the Nα of Ser‐13 in PYY13–36 and then anchoring the N‐terminal segment, e.g. PYY3–12, to the new Lys Nε‐amine. We hypothesized that such modifications would alter the folding of PYY, due to changes in the turn motif, which could change the binding mode to the Y receptor sub‐types and possibly also alter metabolic stability. In structure‐affinity/activity relationship experiments, one series of PYY isoforms displayed equipotency towards the Y receptors. However, an increased Y2 receptor potency for the second series of PYY isoforms resulted in enhanced Y receptor selectivity compared to PYY3–36. Additionally, acute as well as chronic mice studies showed body‐weight‐lowering effects for one of the PYY isoforms, which was also reflected in a reduction of circulating leptin levels. Interestingly, while the stability and pharmacokinetic profile of PYY3–36 and the N‐terminally modified PYY3–36 analogue were identical, only mice treated with the branched analogue showed marked increases in adiponectin levels as well as reductions in non‐esterified free fatty acids and triglycerides. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.