Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension

Cell Metab. 2021 Jun 1;33(6):1155-1170.e10. doi: 10.1016/j.cmet.2021.04.007. Epub 2021 May 4.

Abstract

Pathologies of the micro- and macrovascular systems are a hallmark of the metabolic syndrome, which can lead to chronically elevated blood pressure. However, the underlying pathomechanisms involved still need to be clarified. Here, we report that an obesity-associated increase in serum leptin triggers the select expansion of the micro-angioarchitecture in pre-autonomic brain centers that regulate hemodynamic homeostasis. By using a series of cell- and region-specific loss- and gain-of-function models, we show that this pathophysiological process depends on hypothalamic astroglial hypoxia-inducible factor 1α-vascular endothelial growth factor (HIF1α-VEGF) signaling downstream of leptin signaling. Importantly, several distinct models of HIF1α-VEGF pathway disruption in astrocytes are protected not only from obesity-induced hypothalamic angiopathy but also from sympathetic hyperactivity or arterial hypertension. These results suggest that hyperleptinemia promotes obesity-induced hypertension via a HIF1α-VEGF signaling cascade in hypothalamic astrocytes while establishing a novel mechanistic link that connects hypothalamic micro-angioarchitecture with control over systemic blood pressure.

Keywords: HIF1α-VEGF; angiogenesis; astrocytes; hypertension; hypothalamus; leptin; obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • Astrocytes / pathology
  • Female
  • Hypertension / metabolism*
  • Hypothalamus / metabolism*
  • Hypothalamus / pathology
  • Leptin / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / metabolism*

Substances

  • Leptin