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Why Weight Regain Occurs : Biological adaptations that promoted weight gain initially remain present Appetite and food preoccupation often return when medication stopped Metabolic rate may decrease during weight loss (adaptive thermogenesis) Hormonal changes that defend against weight loss persist Long-Term Management : Most individuals require ongoing medication for sustained weight loss maintenance This is similar to other chronic disease treatments (e.g., blood pressure medications) Obesity is a chronic disease requiring long-term management Strong lifestyle habits help minimize regain but may not prevent it entirely Discuss any plans to discontinue medication with healthcare provider to develop appropriate tapering plan and maintenance strategies

Neuroprotective effects via PI3K/Akt/GSK-3 and IGF-1PI3K-AktmTOR signaling further contribute to reduced muscle degradation and improved protein synthesis

Supplementary information The online version contains supplementary material available at 10.1038/s41421-024-00700-0

Why pulsatile and endogenous matters Because these analogs stimulate the pituitary rather than replacing GH, the resulting secretion tends to preserve the bodys natural pulsatile rhythm and remains subject to normal feedback control somatostatin, IGF-1 negative feedback, and the finite secretory capacity of the gland

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