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Peripheral-specific Y1 receptor antagonism increases thermogenesis and protects against diet-induced obesity

Chenxu Yan1,2, Tianshu Zeng3, Kailun Lee1

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

Nature Communications
|May 12, 2021
PubMed

Insights

Blocking peripheral Y1 receptors (Y1R) enhances energy expenditure and reduces fat mass, offering a potential new obesity treatment. This approach improves glucose homeostasis by targeting Y1R in fat cells.

Area of Science:

  • Metabolism and Endocrinology
  • Obesity Research
  • Adipose Tissue Biology

Background:

  • Obesity arises from an energy intake and expenditure imbalance.
  • Peripheral Y1 receptors (Y1R) are implicated in energy balance regulation.

Purpose of the Study:

  • To investigate the role of peripheral Y1R signaling in controlling energy expenditure (EE).
  • To evaluate the therapeutic potential of selective peripheral Y1R antagonism for obesity and metabolic dysfunction.

Main Methods:

  • Administration of BIBO3304, a non-brain penetrant Y1R antagonist, in mice.
  • Assessment of body weight, energy expenditure, and adipose tissue characteristics (thermogenesis, UCP1, browning).
  • Selective Y1R ablation in adipocytes and analysis of glucose homeostasis and Akt activity in brown adipose tissue (BAT).

Main Results:

  • Selective peripheral Y1R antagonism significantly reduced body weight gain by enhancing EE.
  • Increased thermogenesis in brown adipose tissue (BAT) and white adipose tissue (WAT) browning were observed.
  • Y1R ablation in adipocytes protected against diet-induced obesity and improved glucose homeostasis.

Conclusions:

  • Peripheral Y1R signaling is a key regulator of energy expenditure and fat mass.
  • Selective peripheral Y1R antagonism, exemplified by BIBO3304, represents a promising therapeutic strategy for obesity.
  • Targeting Y1R in adipocytes offers a novel approach to improve metabolic health and combat obesity.

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