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Energy partitioning between fat and bone mass is controlled via a hypothalamic leptin/NPY relay

International Journal of Obesity volume 44, pages 2149–2164 (2020)Cite this article

Subjects

Abstract

Background/objectives

Maintaining energy balance is important to ensure a healthy organism. However, energy partitioning, coordinating the distribution of sufficient energy to different organs and tissues is equally important, but the control of this process is largely unknown. In obesity, an increase in fat mass necessitates the production of additional bone mass to cope with the increase in bodyweight and processes need to be in place to communicate this new weight bearing demand. Here, we investigate the interaction between leptin and NPY, two factors critically involved in the regulation of both energy metabolism and bone mass, in this process.

Methods

We assessed the co-localization of leptin receptors on NPY neurons using RNAScope followed by a systematic examination of body composition and energy metabolism profiling in male and female mice lacking leptin receptors specifically in NPY neurons (Leprlox/lox;NPYCre/+). The effect of short-term switching between chow and high-fat diet was also examined in these mice.

Results

We uncovered that leptin receptor expression is greater on a subpopulation of NPY neurons in the arcuate that do not express AgRP. We further show that Leprlox/lox;NPYCre/+ mice exhibit significantly increased adiposity while bone mass is diminished. These body composition changes occur in the absence of alterations in food intake or energy expenditure, demonstrating a prominent role for leptin signaling in NPY neurons in the control of energy partitioning. Importantly however, when fed a high-fat diet, these mice display a switch in energy partitioning whereby they exhibit a significantly enhanced ability to increase their bone mass to match the increased bodyweight caused by higher caloric intake concurrent with attenuated adiposity.

Conclusions

Taken together, these results demonstrate that leptin signaling in NPY neurons is critical for coordinating energy partitioning between fat and bone mass especially during situations of changes in energy balance.

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Fig. 1: Lepr expression in the mouse brain and generation of Leprlox/lox;NPYCre/+ mice.
Fig. 2: Lack of leptin signaling in NPY neurons results in increased fat mass.
Fig. 3: Energy homeostasis parameters under chow conditions.
Fig. 4: Leptin signaling in NPY neurons controls bone mass.
Fig. 5: Lack of leptin signaling in NPY neurons leads to an attenuation of adiposity under HFD conditions.
Fig. 6: Lack of leptin signaling in NPY neurons leads to increased bone mass under HFD conditions.
Fig. 7: Leptin signaling on NPY neurons regulates energy partitioning and glucose homeostasis.

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Acknowledgements

This work was supported by the National Health and Medical Research Council (NHMRC) of Australia (Grant ID 1156371). We thank the staff of the Garvan Institute Biological Testing Facility and staff of the Australian BioResources for taking care of our test mice.

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Authors and Affiliations

  1. Neuroscience Division, Garvan Institute of Medical Research, St Vincent’s Hospital Sydney, Sydney, NSW, 2010, Australia

    Nicola J. Lee, Yue Qi, Ronaldo F. Enriquez, Ireni Clarke, Chi Kin Ip & Herbert Herzog

  2. St Vincent’s Clinical School, UNSW Sydney, Sydney, NSW, Australia

    Nicola J. Lee, Chi Kin Ip, Paul A. Baldock & Herbert Herzog

  3. Bone Division, Garvan Institute of Medical Research, St Vincent’s Hospital Sydney, Sydney, NSW, 2010, Australia

    Natalie Wee & Paul A. Baldock

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Lee, N.J., Qi, Y., Enriquez, R.F. et al. Energy partitioning between fat and bone mass is controlled via a hypothalamic leptin/NPY relay. Int J Obes 44, 2149–2164 (2020). https://doi.org/10.1038/s41366-020-0550-6

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