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Physiology and Biochemistry

Leptin signaling in vagal afferent neurons supports the absorption and storage of nutrients from high-fat diet

International Journal of Obesity volume 45, pages 348–357 (2021)Cite this article

Subjects

Abstract

Objective

Activation of vagal afferent neurons (VAN) by postprandial gastrointestinal signals terminates feeding and facilitates nutrient digestion and absorption. Leptin modulates responsiveness of VAN to meal-related gastrointestinal signals. Rodents with high-fat diet (HF) feeding develop leptin resistance that impairs responsiveness of VAN. We hypothesized that lack of leptin signaling in VAN reduces responses to meal-related signals, which in turn decreases absorption of nutrients and energy storage from high-fat, calorically dense food.

Methods

Mice with conditional deletion of the leptin receptor from VAN (Nav1.8-Cre/LepRfl/fl; KO) were used in this study. Six-week-old male mice were fed a 45% HF for 4 weeks; metabolic phenotype, food intake, and energy expenditure were measured. Absorption and storage of nutrients were investigated in the refed state.

Results

After 4 weeks of HF feeding, KO mice gained less body weight and fat mass that WT controls, but this was not due to differences in food intake or energy expenditure. KO mice had reduced expression of carbohydrate transporters and absorption of carbohydrate in the jejunum. KO mice had fewer hepatic lipid droplets and decreased expression of de novo lipogenesis-associated enzymes and lipoproteins for endogenous lipoprotein pathway in liver, suggesting decreased long-term storage of carbohydrate in KO mice.

Conclusions

Impairment of leptin signaling in VAN reduces responsiveness to gastrointestinal signals, which reduces intestinal absorption of carbohydrates and de novo lipogenesis resulting in reduced long-term energy storage. This study reveals a novel role of vagal afferents to support digestion and energy storage that may contribute to the effectiveness of vagal blockade to induce weight loss.

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Fig. 1: KO mice were resistant to high-fat diet-induced obese phenotype.
Fig. 2: No difference in overall food intake and energy expenditure.
Fig. 3: Decreased absorption of monosaccharide in the jejunum in KO mice.
Fig. 4: Delayed storage of hepatic glycogen and decreased lipogenesis in liver KO mice.
Fig. 5: Illustration of the effect of leptin signaling in VAN on supporting nutrients absorption and long-term energy storage during HF feeding.

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Acknowledgements

This work was funded by grant NIHDDK 41004 (HER) and by the Australian Research Council Discovery Project (DP140102203). Additional support was provided by the UC Davis MMPC Energy Balance, Exercise, & Behavior Core (NIH grant U24-DK092993, RRID: SCR_015357 and SCR_015364) and the University of Cincinnati MMPC (Non-invasive measurement of intestinal fat absorption). We acknowledge Dr Ingrid Brust-Mascher, Department of Anatomy, Physiology & Cell Biology, UC Davis for image analysis of consulting. The EE ANCOVA analysis done for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (MMPC, www.mmpc.org) using their Energy Expenditure Analysis page (http://www.mmpc.org/shared/regression.aspx) and supported by grants DK076169 and DK115255”.

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Authors and Affiliations

  1. School of Veterinary Medicine, University of California Davis, Davis, CA, USA

    Kuei-Pin Huang, Michael L. Goodson, Wendie Vang & Helen E. Raybould

  2. Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia

    Hui Li & Amanda J. Page

  3. South Australian Health and Medical Research Institute, Adelaide, SA, Australia

    Hui Li & Amanda J. Page

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KPH—design of the work; acquisition of data; data analysis; interpretation of data; drafted and revised manuscript; approved final version. MLG—design of the work; acquisition of data; approved final version. WV—acquisition of data; data analysis; approved final version. HL—acquisition of data; data analysis; interpretation of data; approved final version. AJP—design of the work; interpretation of data; revised manuscript; approved final version. HER—design of the work; interpretation of data; drafted and revised manuscript; submitted final version.

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Correspondence to Helen E. Raybould.

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Huang, KP., Goodson, M.L., Vang, W. et al. Leptin signaling in vagal afferent neurons supports the absorption and storage of nutrients from high-fat diet. Int J Obes 45, 348–357 (2021). https://doi.org/10.1038/s41366-020-00678-1

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