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Physiology and biochemistry

Metformin effectively restores the HPA axis function in diet-induced obese rats

International Journal of Obesity volume 45, pages 383–395 (2021)Cite this article

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Abstract

Introduction

The hypothalamo-pituitary-adrenal (HPA) axis is perturbed in obesity. We previously reported presence of leptin resistance in the brainstem and uncoupling between central noradrenergic tone and the HPA axis in obesity-prone (DIO) rats. Metformin is shown to lower body weight and adiposity, but the underlying mechanism is unclear. We hypothesized that this is associated with restored HPA axis function.

Methods

Adult male DIO rats were placed on either a regular chow or HF diet for 7 weeks. Starting week 4, the animals were given either a low dose (60 mg/kg) or high dose (300 mg/kg) of metformin in drinking water. In addition to body weight and feeding, we examined different arms of the HPA axis to test if metformin can reinstate its function and coupling. To understand potential mechanisms, leptin signaling in the brainstem and circulating free fatty acid levels were also assessed.

Results

Metformin treatment lowered weight gain, fat mass, caloric intake, and serum leptin levels. HPA axis activity as determined by corticotropin-releasing hormone in the median eminence and serum corticosterone was decreased by metformin in a dose-dependent manner, and so was norepinephrine (NE) in the paraventricular nucleus. Importantly, metformin completely normalized the NE-HPA axis uncoupling. While brainstem pSTAT-3 and SOCS-3, key markers of leptin signaling, were not different between groups, circulating saturated and unsaturated free fatty acids were reduced in HF-fed, metformin-treated animals.

Conclusions

These findings suggest that oral metformin can successfully correct HPA axis dysfunction that is associated with lowered circulating free fatty acids in DIO rats, thereby uncovering a novel effect of metformin in the treatment of obesity.

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Fig. 1: Study design.
Fig. 2: BW, caloric intake, and feed efficiency.
Fig. 3: Oral metformin treatment decreases fat mass and circulating leptin in HF-fed DIO rats.
Fig. 4: Metformin dose-dependently lowers PVN NE and suppresses the HPA axis.
Fig. 5: Metformin effectively rescues the coupling between PVN NE and the HPA axis in DIO rats.
Fig. 6: No change in brainstem leptin signaling following metformin supplementation.
Fig. 7: Metformin treatment reduces circulating free fatty acids in HF-fed DIO rats.

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Acknowledgements

We would like to thank Ms. Katrina Linning for her excellent technical assistance and for maintaining the rat colony.

Funding

This study was supported in part by NIH grant R01 AG027697 to PSM and NSF grant IBN0236385 to SMJM and PSM. ACS was supported by Biomedical Health Research Initiative grant, MSU.

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Authors and Affiliations

  1. Department of Nutritional Sciences, College of Human Sciences, Texas Tech University, Lubbock, TX, 79409, USA

    Andrew C. Shin

  2. Neuroscience Program, Michigan State University, East Lansing, MI, 48824, USA

    Andrew C. Shin, Sheba M. J. MohanKumar & Puliyur S. MohanKumar

  3. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, 48824, USA

    Priya Balasubramanian & Sheba M. J. MohanKumar

  4. Department of Veterinary Biosciences and Diagnostic Imaging, University of Georgia, Athens, GA, 30602, USA

    Pavan Suryadevara, Sheba M. J. MohanKumar & Puliyur S. MohanKumar

  5. Diagnostic Center for Population and Animal Health, Michigan State University, East Lansing, MI, 48824, USA

    Justin Zyskowski & Thomas H. Herdt

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  1. Andrew C. Shin
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Shin, A.C., Balasubramanian, P., Suryadevara, P. et al. Metformin effectively restores the HPA axis function in diet-induced obese rats. Int J Obes 45, 383–395 (2021). https://doi.org/10.1038/s41366-020-00688-z

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