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Importantly, the EWcp UCN1/CART-expressing neurons project to reward and addiction-related brain areas including the ventral tegmental area (VTA), dorsal raphe nucleus (DRN), central nucleus of amygdala (CeA) and the lateral septum (LS) 3

The title for Figure 4 should be reconsidered as the term "mutually opposite signal modulation" is unclear and/or does not reflect the description to follow. Response: We have replaced the term mutually opposite signal modulation with: amplification of MC3R signaling and attenuation of GHSR1a signaling For Figure 5, the figure legend should clarified if 5-HT2c-GHSR1a dimerization produces reduced Ca++ accumulation with (as appears to be implied by the figure) or without ligand for each receptor. Response: To make it clearer that the 5-HT2C ligand is not required, while the ghrelin ligand is, we have changed the description to read: When dimerized with 5-HT2C, GHSR1a displays a 65% reduction in ghrelin-induced Ca2+ accumulation, with this effect not requiring the presence of a 5-HT2C ligand. Reviewer #2: The review includes an excellent explanation of GSHR1a dimerization with other receptors at the cellular and molecular level and also does a good job of explaining technical aspects of this type of work

(2) Downstream protection with cartilage-building substrates (e.g., collagen peptides, vitamin D) to enhance matrix integrity (11, 12)

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Site Rotation Strategy: Maintain a rotation pattern across multiple sites (e.g., left abdomen right abdomen left thigh right thigh)