Physical #Fitness with #Exercise and #GLP1 Receptor Agonist Treatment Alone or Combined After Diet-Induced #WeightLoss: A Secondary Analysis of a Randomized Controlled Trial in Adults with #Obesity
Our latest publication in Sports Medicine
Physiological and molecular characterization of individuals carrying a diabetogenic mtDNA mutation establishes a mitochondrial basis for insulin resistance in humans
👇Check out our preprint on @medrxivpreprint.bsky.social
💬Comments and feedback are very welcome
📄 New preprint
Using deep physiological and molecular phenotyping in individuals carrying a diabetogenic mtDNA mutation, we probe whether, which, and how mitochondrial defects drive insulin resistance in humans.
👇 Link in first comment
#Physiology #Diabetes #Mitochondria #Metabolism
✨Proud moment at #EASD2025
Tue L. Nielsen presented our MITO-DYS-IR study results in the plenary hall, uncovering the causal role of #muscle #mitochondrial defects in #diabetes pathophysiology
Grateful to our collaborators and @easdnews.bsky.social Early Career Academy for the Best Abstract Award
If you’re at #EASD2025 and interested in potential mechanisms that protect against obesity, don’t miss:
“LBA SO 02 – Thinking Big About Treating Obesity”
📍 Short Oral Station 23 (Hall C)
📅 Tuesday, 16 Sept
⏰ 13:15
@easdnews.bsky.social
A big day for preventing mitochondrial diseases from transmitting to the next generation
www.nature.com/articles/d41...
www.nejm.org/doi/full/10....
www.nejm.org/doi/full/10....
www.nejm.org/doi/full/10....
Here it is proposed that halofuginone, a FDA–approved anti-scleroderma and antiprotozoal drug, is a promising anti-#obesity agent acting via FGF-21 and GDF-15 in preclinical mouse and pig models www.science.org/doi/10.1126/...
Reducing the mitochondrial oxidative burden alleviates lipid-induced muscle insulin resistance in humans
In our latest study, we provide mechanistic evidence implicating mitochondrial ROS in the development of muscle insulin resistance in hyperlipidemic states such as obesity.
1/7 🧵👇
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.
Kicking off 2025 with a highlight from our 2024 study in #CellReportsMedicine @cellpress.bsky.social
We uncovered the potential role of a metabokine-sphingolipid axis in sustaining weight loss in humans with #obesity.
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Hi Christian, would appreciate being added
Please, add me
Views about the causes of obesity have polarised. Characterised by low carb and energy balance models. Last year NovoNordisk invited the protagonists of these models to Copenhagen to discuss commonalities and differences. The resultant paper has now been published in Nature Metabolism rdcu.be/dZryb
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.
Reducing the mitochondrial oxidative burden alleviates lipid-induced muscle insulin resistance in humans
In our latest study, we provide mechanistic evidence implicating mitochondrial ROS in the development of muscle insulin resistance in hyperlipidemic states such as obesity.
1/7 🧵👇
A mechanism for why durable weight loss is so difficult: epigenetic memory of fat cells
www.nature.com/articles/s41...
