DACRA induces profound weight loss, satiety control, and increased mitochondrial respiratory capacity in adipose tissue

Emilie A. Petersen*, Ida Blom, Simone A. Melander, Mays Al-Rubai, Marina Vidotto, Louise T. Dalgaard, Morten A. Karsdal, Kim Henriksen, Steen Larsen, Anna T. Larsen

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Background and objectives: Dual amylin and calcitonin receptor agonists (DACRAs) are therapeutic candidates in the treatment of obesity with beneficial effects on weight loss superior to suppression of food intake. Hence, suggesting effects on energy expenditure by possibly targeting mitochondria in metabolically active tissue. Methods: Male rats with HFD-induced obesity received a DACRA, KBP-336, every third day for 8 weeks. Upon study end, mitochondrial respiratory capacity (MRC), - enzyme activity, - transcriptional factors, and -content were measured in perirenal (pAT) and inguinal adipose tissue. A pair-fed group was included to examine food intake-independent effects of KBP-336. Results: A vehicle-corrected weight loss (23.4 ± 2.8%) was achieved with KBP-336, which was not observed to the same extent with the food-restricted weight loss (12.4 ± 2.8%) (P < 0.001). Maximal coupled respiration supported by carbohydrate and lipid-linked substrates was increased after KBP-336 treatment independent of food intake in pAT (P < 0.01). Moreover, oligomycin-induced leak respiration and the activity of citrate synthase and β-hydroxyacetyl-CoA-dehydrogenase were increased with KBP-336 treatment (P < 0.05). These effects occurred without changes in mitochondrial content in pAT. Conclusions: These findings demonstrate favorable effects of KBP-336 on MRC in adipose tissue, indicating an increased energy expenditure and capacity to utilize fatty acids. Thus, providing more mechanistic insight into the DACRA-induced weight loss. (Figure presented.)
Original languageEnglish
JournalInternational Journal of Obesity
Volume48
Issue number10
Pages (from-to)1421-1429
Number of pages9
ISSN0307-0565
DOIs
Publication statusPublished - Oct 2024

Bibliographical note

The datasets generated during and analyzed during the current studies are available from the corresponding author on reasonable request.

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