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Small extracellular vesicle targeting of hypothalamic AMPKα1 promotes weight loss in leptin receptor deficient mice

Edward Milbank1, Nathalia Dragano1, Xavi Vidal-Gómez2

  • 1Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain.

Metabolism: Clinical and Experimental
|November 24, 2022
PubMed
Abstract

Insights

Small extracellular vesicles delivering a dominant-negative mutant of AMP-activated protein kinase alpha 1 (AMPKα1-DN) to the hypothalamus reduced obesity in mice. This novel approach offers a potential therapy for leptin receptor (LEPR) deficiency.

Area of Science:

  • Neuroscience
  • Metabolic Research
  • Biotechnology

Background:

  • Leptin receptor (LEPR) deficiency causes severe obesity and metabolic dysfunction.
  • Limited therapeutic strategies exist for LEPR deficiency-induced obesity.

Purpose of the Study:

  • To investigate the efficacy of neuronal-targeted small extracellular vesicles (sEVs) delivering a dominant-negative mutant of AMP-activated protein kinase alpha 1 (AMPKα1-DN) in a mouse model of obesity.
  • To specifically modulate AMPK activity in SF1 cells within the ventromedial nucleus of the hypothalamus (VMH).

Main Methods:

  • db/db mice and wildtype controls were treated with sEVs carrying a plasmid encoding SF1-driven AMPKα1-DN.
  • Systemic administration of sEVs targeted hypothalamic SF1 neurons.
  • Metabolic phenotyping was performed to assess treatment effects.

Main Results:

  • Mice treated with SF1-AMPKα1-DN loaded sEVs exhibited significant weight loss independent of food intake.
  • Reduced adiposity, increased sympathetic tone, and enhanced brown adipose tissue (BAT) thermogenesis were observed.
  • White adipose tissue (WAT) browning was also promoted.

Conclusions:

  • Hypothalamic AMPK modulation via sEV-based technology presents a promising therapeutic strategy for genetic obesity, including LEPR deficiency.
  • Targeted delivery of therapeutic agents to the hypothalamus can effectively combat metabolic disorders.
Keywords:
AMPKHypothalamusLeptin receptor deficiencydb/db micesEVs

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