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. 2020 Mar 2;10(1):3821.
doi: 10.1038/s41598-020-60518-0.

Modulation of feeding behavior and metabolism by dynorphin

Aishwarya Ghule  1 , Ildiko Rácz  1   2 , Andras Bilkei-Gorzo  3 , Este Leidmaa  1 , Meike Sieburg  1   4 , Andreas Zimmer  1
Affiliations

Modulation of feeding behavior and metabolism by dynorphin

Aishwarya Ghule et al. Sci Rep. .

Abstract

The neuronal regulation of metabolic and behavioral responses to different diets and feeding regimens is an important research area. Herein, we investigated if the opioid peptide dynorphin modulates feeding behavior and metabolism. Mice lacking dynorphin peptides (KO) were exposed to either a normal diet (ND) or a high-fat diet (HFD) for a period of 12 weeks. Additionally, mice had either time-restricted (TR) or ad libitum (AL) access to food. Body weight, food intake and blood glucose levels were monitored throughout the 12-week feeding schedule. Brain samples were analyzed by immunohistochemistry to detect changes in the expression levels of hypothalamic peptides. As expected, animals on HFD or having AL access to food gained more weight than mice on ND or having TR access. Unexpectedly, KO females on TR HFD as well as KO males on AL ND or AL HFD demonstrated a significantly increased body weight gain compared to the respective WT groups. The calorie intake differed only marginally between the genotypes: a significant difference was present in the female ND AL group, where dynorphin KO mice ate more than WT mice. Although female KO mice on a TR feeding regimen consumed a similar amount of food as WT controls, they displayed significantly higher levels of blood glucose. We observed significantly reduced levels of hypothalamic orexigenic peptides neuropeptide Y (NPY) and orexin-A in KO mice. This decrease became particularly pronounced in the HFD groups and under AL condition. The kappa opiod receptor (KOR) levels were higher after HFD compared to ND feeding in the ventral pallidum of WT mice. We hypothesize that HFD enhances dynorphin signaling in this hedonic center to maintain energy homeostasis, therefore KO mice have a more pronounced phenotype in the HFD condition due to the lack of it. Our data suggest that dynorphin modulates metabolic changes associated with TR feeding regimen and HFD consumption. We conclude that the lack of dynorphin causes uncoupling between energy intake and body weight gain in mice; KO mice maintained on HFD become overweight despite their normal food intake. Thus, using kappa opioid receptor agonists against obesity could be considered as a potential treatment strategy.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Body weight change of female and male mice receiving normal diet (ND) (A,B) or high fat (C,D) diet (HFD). Female and male mice, ND and HFD groups were analyzed separately. The animal numbers in the experimental groups were as followes: n = 7 in male ND AL KO, HFD TR WT and HFD AL KO; n = 8 in female ND TR WT, HFD TR KO, HFD AL WT, HFD AL KO and in males in the ND TR WT, ND TR KO, ND AL WT, HFD TR KO and HFD AL WT. N = 9 was used in female ND TR KO, ND AL WT and ND AL KO; n = 10 in female HFD TR WT. *p < 0.05; **p < 0.01; ***p < 0.001 difference according to Šidákś test between WT and KO in the TR (grey symbols) and AL (light blue) groups. +p < 0.05; ++p < 0.01; +++p < 0.001 difference between TR and AL groups according to Šidákś test in WT (black or dark blue) or KO (grey or light blue) mice. Symbols represent means, whiskers SEM.
Figure 2
Figure 2
Food intake in WT and KO animals maintained on ad libitum (AL) or time restricted (TR) feeding schedules during 12-week feeding regimen. Food intake in female and male mice maintained on a ND are shown on (A,B), respectively, whereas, female and male mice maintained on a HFD schedule are shown on (C,D), respectively. Symbols represent means, whiskers SEM. *p < 0.05; **p < 0.01 according to Šidákś test compared to week 1 within the WT (black symbols) or KO (blue symbols) groups.
Figure 3
Figure 3
Blood glucose levels in mice kept on TR feeding protocol, receiving ND (females A, males B) or HFD (females C, males D) diet. Blood glucose levels of mice kept on AL feeding receiving ND is shown at panel E (females), F (males) or HFD at pane G (females) and H (males). *p < 0.05; **p < 0.01; ***p < 0.001 difference compared to week 3 from the same genotype according to Šidákś test. #p < 0.05 difference between WT and KO according to Šidákś test. Bars represent mean values, whiskers SEM.
Figure 4
Figure 4
Immunohistochemical analysis of hypothalamic peptide NPY expression in the ARC. Region framed in red on the brain picture indicates the site of histological recordings. The mean signal intensity was calculated from sections from 3–4 mice per group. Female animals on a normal diet (ND) are shown in (A), males in (B). Female animals on a high fat diet (HFD) are shown in (C), males in (D). The scale bar represents 250 µm. *p < 0.05, **p < 0.01, ***p < 0.001 difference between the genotypes having the same feeding schedule; +p < 0.05, ++p < 0.01, +++p < 0.0001 difference between the feeding schedule within the same genotypes, each using Šidákś test.
Figure 5
Figure 5
Immunohistochemical analysis of orexin-A expression in the lateral hypothalamus. Region framed in red on the brain picture indicates the site of histological recordings. The mean integrated signal density was calculated from sections from 3–4 mice per group. Female animals on normal diet (ND) are shown in (A), males in (B). Female animals on high fat diet (HFD) are shown in (C), males in (D). The scale bar represents 250 µm. ***p < 0.001 difference between the genotypes having the same feeding schedule +++p < 0.001 difference between the feeding schedule within the same genotypes, each using Šidákś test.
Figure 6
Figure 6
Immunohistochemical analysis of KOR and Pdyn expression. Region framed in red on the brain image indicates the site of histological analysis. The mean integrated signal density shown at the left panels was calculated from 3–4 male wild-type mice per group (average of 4–6 sections per animal), right panels show representative images. The scale bar represents 50 µm. *p < 0.05 difference between the ND and HFD groups using Studentś t-test.
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