Evaluation of VGF peptides as potential anti-obesity candidates in pre-clinical animal models

The molecular identity of the TLQP-21 peptide receptor

“…While, they provide valuable insights, unfortunately they are limited in scope due to partial validation or significant cross-reactivity with overlapping VGF fragments including the TLQP-62 precursor, a peptide for which a cognate receptor has not been identified yet and which shows a pharmacology often inconsistent with TLQP-21. Indeed, while TLQP-21 and TLQP-62 treatment resulted in overlapping, but not identical, reduction in neuropathology in 5xFAD model of Alzheimer`s disease [ 19 ] and thermal and mechanical hypersensitivity [ 20 ], several studies showed non-overlapping and potentially opposing effects of either the two peptides or non-cross reactive antibodies directed specifically to TLQP-21 or TLQP-62, including in: contextual fear conditioning memory [ 21 ], behavior in depression-related tests like the forced swim test and social interaction test [ 22 ] and the firing rate of hypothalamic neuronal networks [ 23 ]. Studies in insulinoma [ 14 ] and CHO cells [ 24 ], revealed different potencies of the two peptides, and moreover, stimulation of insulin secretion by TLQP-62 in insulinoma cells was not blocked by the C3aR1 antagonist SB290157 [ 14 ].…”

“…Moreover, experiments conducted on lean hamsters through TLQP-21 administration exposed to short photoperiods caused reduced food intake, while the same was not seen in hamsters exposed to long photoperiods [ 18 , 32 ]. At variance, a recent report showed no anti-obesity effect of TLQP-21 in diet-induced obese mice [ 23 ]. Several methodological differences must be noted among these studies, including the duration of high-fat diet (HFD) (9 [ 28 ] vs 32 [ 23 ] weeks) and peptide infusion (28 [ 28 ] vs 11 days [ 23 ]).…”

“…At variance, a recent report showed no anti-obesity effect of TLQP-21 in diet-induced obese mice [ 23 ]. Several methodological differences must be noted among these studies, including the duration of high-fat diet (HFD) (9 [ 28 ] vs 32 [ 23 ] weeks) and peptide infusion (28 [ 28 ] vs 11 days [ 23 ]). Furthermore, in the recent study [ 23 ], but in no previous study, TLQP-21 was dissolved in Polysorbate-80 (Tween-80) a solvent known to cause inflammation and metabolic syndrome [ 42 ] and to increase C3a activation (the originally identified ligand for C3aR1) [ 43 , 44 ]; overall, this suggests a potential interference of Tween-80 with the mechanism of action of TLQP-21 which remains to be investigated.…”

European Society of Toxicologic Pathology (Pathology 2.0 Molecular Pathology Special Interest Group): Review of In Situ Hybridization Techniques for Drug Research and Development

“…IHC and ISH contributed significantly to animal model characterization for validation of pathogenesis and target pathways to be intervened pharmacologically. [147][148][149] Similarly, in vaccine development, ISH can be very useful to monitor viral pathogenesis in animal models. Using ISH, key data were provided to show that the cynomolgus monkey was as good as, if not better than the rhesus monkey, to model SARS-Cov-2 infection and disease.…”

Non‐Cardiotoxic Tetradecanoic Acid‐2,4‐Dinitrophenol Ester Nanomicelles in Microneedles Exert Potent Anti‐Obesity Effect by Regulating Adipocyte Browning and Lipogenesis

“…[19,20] To further restrict anti-obesity drugs in adipose tissue, locally applied hydrogels and in situ injection of drugs were proposed, which still possess limits, such as complicated preparation and limited adipose tissue accumulation. [21,22] In recent years, the microneedles (MN) delivery system represents a non-invasive topical drug delivery approach, which could increase patients' compliance; and thus, facilitate its application. [23] To date, the spatial precision of MN has been applied on various tissues, including vascular and ocular tissues and breast tumors.…”