The review focuses on the signaling cross-talk of insulin and leptin regarding the regulation of metabolic homeostasis. The review is well-written, very informative, and providing excellent discussion. I really enjoyed reading it. I don’t believe that the authors need to change the structure, and I felt that it is almost ready to be published; however, I have a couple of comments which may benefit readers. My comments are followings;

(1a) Authors described the role of WNT/β-catenin signaling in leptin’s insulin-sensitizing effects. I was wondering whether central insulin effects (food intake, glucose metabolism, etc.) are also mediated by WNT/β-catenin signaling as PI3K is important for insulin actions in the regulation of glucose metabolism. Authors put the subtitle “WNT/β-catenin signaling as an integrator of central insulin and leptin action on energy homeostasis”; however, the references cited by authors only described central leptin’s action and not central insulin in the brain; therefore, it is unclear whether WNT/β-catenin is the integrator of leptin and insulin singling in the brain.

(1b)The authors described that WNT/β-catenin expression levels and leptin signaling are correlated, and leptin injections can modulate WNT/β-catenin expression levels (references numbers 79 and 107). I was wondering if there are any papers demonstrating the causality of leptin and WNT/beta-catenin singling rather than the correlations by any means (like either pharmacological or genetic studies). For instance, the authors pinpointed the importance of POMC and AgRP neurons regarding glucoregulatory effects of leptin. Thus, one can imagine experiments investigating whether knockout of one of WNT/β-catenin (e.g., TCL-7) signaling from AgRP or POMC neurons may hamper the leptin’s effects on glucose metabolism. If there are no such investigations on leptin and insulin, it appears to be hard to claim that “WNT/β-catenin signaling as an integrator of central insulin and leptin action on energy homeostasis.”

(2a) The authors described that the circadian clock regulates leptin sensitivity likely via the GABAergic inputs from the SCN. However, it is unclear how the circadian clock affects leptin sensitivity in the ARC neurons (I guess AgRP/POMC neurons in the ARC or ARC LEPRs-expressing neurons) in the brain. Some papers suggested that the central leptin sensitivity issue likely comes from the defected transportation system of leptin instead of the signaling pathways in the ARC. It is curious how the SCN→ARC projections can disrupt leptin sensitivity or potentially, the transportation mechanisms of leptin. It will be helpful if authors can propose the potential mechanism by which the circadian clock can regulate leptin sensitive in the brain (or ARC). Is there any signaling pathway such as WNT/β-catenin in the ARC neurons involved? For instance, does the circadian clock regulate/disrupt WNT/β-catenin signaling in the ARC?

(2b) The authors did not describe insulin signaling in the brain in terms of the circadian clock, but it may be great if authors can address how the circadian clock also affects insulin actions in the brain/peripheral regarding glucose homeostasis.

The authors addressed the comments from the reviewers.