Despite the increasing prevalence
of obesity, the current medications,
which act indirectly on the central nervous system to suppress appetite
or on the gastrointestinal tract to inhibit fat absorption, suffer
from poor effectiveness and side effects. Here, we developed a transdermal
mild photothermal therapy directly acting on the root of evil (subcutaneous
white adipose depot) to induce its ameliorating remodeling (browning,
lipolysis, and apoptosis), based on the injectable thermoresponsive
hydrogel encapsulated with copper sulfide nanodots. Further, combining
pharmaceutical therapy with codelivery of mirabegron leads to a strong
therapeutic synergy. This method not only ensures high effectiveness
and low side effects due to localized and targeted application but
also remotely creates significant improvements in systemic metabolism.
Specifically, as compared to the untreated group, it totally inhibits
obesity development in high-fat-diet fed mice (15% less in body weight)
with decreased masses of both subcutaneous (40%) and visceral fats
(54%), reduced serum levels of cholesterol (54%)/triglyceride (18%)/insulin
(74%)/glucose (45%), and improved insulin sensitivity (65% less in
insulin resistance index). This self-administrable method is amenable
for long-term home-based treatment. Finally, multiple interconnected
signaling pathways are revealed, providing mechanistic insights to
develop effective strategies to combat obesity and associated metabolic
disorders.