10/ We propose that the metabokine-sphingolipid axis plays a physiological role in sustaining weight loss in humans with obesity.

9/ Our findings indicate that regardless of the treatment, weight-loss maintenance and weight regain are associated with distinct changes in circulating FGF21, adiponectin, leptin, and ceramides.

8/ We found that FGF21 and leptin were downregulated, whereas adiponectin was upregulated in weight maintainers vs. regainers.
Likewise, a multitude of sphingolipid species were differentially regulated in weight maintainers vs. regainers.

7/ To interrogate the putative contribution of metabokines and sphingolipids to sustained weight loss per se independent of the weight-loss maintenance treatment, we performed subgroup analyses of participants who either maintained or regained weight during the weight-loss maintenance phase.

6/ We show sphingolipidome-wide remodeling in response to diet-induced weight loss as well as to weight-loss maintenance treatments.
Remarkably, the initial weight loss and the subsequent weight-loss maintenance phase evoked divergent alterations in a subset of ceramides causally linked to obesity.

5/ Given the interplay between metabokines and #ceramides, we explored whether the observed alterations in circulating metabokines were associated with changes in the plasma sphingolipid profile.

4/ As the metabolic effects of FGF21 and GDF15 are partly mediated by #adiponectin and #leptin, we quantified these adipose-derived metabokines and reported that their circulating profiles were ameliorated following weight-loss maintenance with exercise, GLP-1 analog, and their combined treatment.

3/ First, we focused on #FGF21 and #GDF15, two metabokines affecting energy balance.
We found that GDF15 transiently increased upon diet-induced weight loss whereas FGF21 decreased following weight-loss maintenance with combined exercise and GLP-1 analog.

2/ Through exploratory analyses of a four-arm RCT(www.nejm.org/doi/10.1056/NEJMoa2028198), we profiled circulating metabokines and sphingolipids in adults with obesity undergoing an initial weight loss and subsequent weight-loss maintenance phase with #exercise, and/or #GLP-1 analog treatment.

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7/ Looking forward to sharing new findings on the role of #mitochondria in human #diabetes & #obesity from ongoing physiological studies in individuals with genetic mitochondrial defects.

6/ Last, through ex vivo studies in human skeletal muscle fibers, we show that selective targeting of mitochondrial redox state by mtAO partly rescues lipid-induced impairments in mitochondrial bioenergetics.

5/ Through complementary in vitro studies,
we confirmed that disrupted GLUT4 trafficking is a key molecular mechanism by which mitochondrial oxidants impair muscle insulin action.

4/ Mechanistically, the insulin-sensitizing effect of mtAO was linked to i) augmented insulin-stimulated GLUT4 translocation and ii) reduced mitochondrial oxidative burden in skeletal muscle under lipid overload.

3/ Through insulin clamp studies combining infusion of a lipid overload with intake of a mitochondria-targeted antioxidant (mtAO), we show that selective modulation of mitochondrial redox state enhances insulin-stimulated muscle glucose uptake during lipid oversupply.

2/ Inspired by prior preclinical work (shorturl.at/ss23L & shorturl.at/MF3vb),
we employed an in vivo mechanistic approach to interrogate whether the causal link between mitochondrial oxidative stress and insulin resistance translates to humans.