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Animal Models

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

International Journal of Obesity volume 48, pages 1421–1429 (2024)Cite this article

Subjects

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.

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Fig. 1: Changes in body weight, food intake, and adiposity.
Fig. 2: Mitochondrial respiratory capacity in adipose tissue.
Fig. 3: Mitochondrial enzyme activity, - transcriptional factors, and - content in adipose tissue.

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Data availability

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

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Author information

Authors and Affiliations

  1. Nordic Bioscience, Herlev, Denmark

    Emilie A. Petersen, Simone A. Melander, Mays Al-Rubai, Marina Vidotto, Morten A. Karsdal, Kim Henriksen & Anna T. Larsen

  2. Xlab, Center for Healthy Aging, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

    Emilie A. Petersen, Ida Blom & Steen Larsen

  3. Department of Science and Environment, Roskilde University, Roskilde, Denmark

    Mays Al-Rubai, Louise T. Dalgaard & Kim Henriksen

  4. KeyBioscience AG, Stans, Switzerland

    Morten A. Karsdal & Kim Henriksen

  5. Department of Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland

    Steen Larsen

  6. Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery M, Copenhagen University Hospital – Bispebjerg and Frederiksberg, Copenhagen, Denmark

    Steen Larsen

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Contributions

Emilie A. Petersen designed and performed the animal study, performed analyses, and wrote the manuscript. Ida Blom, Simone A. Melander, Mays Al-Rubai, Marina Vidotto, and Louise T. Dalgaard performed analyses. Morten A. Karsdal assisted with study design and data interpretation. Kim Henriksen, Steen Larsen, and Anna T. Larsen: assisted with study design, data interpretation, and manuscript writing. All authors approved the final version of the manuscript.

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Correspondence to Emilie A. Petersen.

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Competing interests

We acknowledge the Danish Innovation Foundation and The Danish Research Foundation for funding. MAK and KH own stock in Nordic Bioscience A/S. EAP, ATL, MAK, and KH are employed by Nordic Bioscience A/S.

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Petersen, E.A., Blom, I., Melander, S.A. et al. DACRA induces profound weight loss, satiety control, and increased mitochondrial respiratory capacity in adipose tissue. Int J Obes 48, 1421–1429 (2024). https://doi.org/10.1038/s41366-024-01564-w

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