Abstract
Abstract
Diet-induced obesity is increasingly understood as a disorder of central
regulatory failure rather than simple energy imbalance. Two
mechanisms—impaired hypothalamic autophagy and epigenetic reprogramming
of feeding-regulatory genes—have been independently implicated in
perpetuating obesity, yet their mechanistic intersection remains poorly defined.
This perspective proposes that these processes are not parallel phenomena but
components of a single self-reinforcing autophagy–epigenome axis
(presented here as a working hypothesis) governed by shared nutrient-sensing
hubs (mechanistic target of rapamycin complex 1, AMP-activated protein kinase,
and sirtuin 1). In this model, chronic caloric excess simultaneously suppresses
autophagic flux and induces epigenetic silencing of autophagy regulators,
potentially creating a feed-forward loop that locks hypothalamic neurons into a
pro-inflammatory, orexigenic state resistant to dietary normalization. The
frequent weight regain observed after glucagon-like peptide-1 receptor agonist
discontinuation—despite these agents’ demonstrated capacity to
enhance central autophagy and suppress neuroinflammation—raises the
possibility that current pharmacotherapies may suppress downstream consequences
without erasing the underlying epigenetic code. This perspective synthesizes
preclinical and emerging translational evidence to argue that durable obesity
treatment will require interventions capable of simultaneously restoring
autophagic flux and reversing epigenetic modifications within hypothalamic
feeding circuits, and identifies critical knowledge gaps that must be addressed
to advance this paradigm from a bench to a bedside.