Sodium-glucose cotransporter 2 inhibitor ameliorates high fat diet-induced hypothalamic-pituitary-ovarian axis disorders

J Physiol. 2022 Nov;600(21):4549-4568. doi: 10.1113/JP283259. Epub 2022 Sep 20.


High-fat diet (HFD) consumption is known to be associated with ovulatory disorders among women of reproductive age. Previous studies in animal models suggest that HFD-induced microglia activation contributes to hypothalamic inflammation. This causes the dysfunction of the hypothalamic-pituitary-ovarian (HPO) axis, leading to subfertility. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of lipid-soluble antidiabetic drugs that target primarily the early proximal tubules in kidney. Recent evidence revealed an additional expression site of SGLT2 in the central nervous system (CNS), indicating a promising role of SGLT2 inhibitors in the CNS. In type 2 diabetes patients and rodent models, SGLT2 inhibitors exhibit neuroprotective properties through reduction of oxidative stress, alleviation of cerebral atherosclerosis and suppression of microglia-induced neuroinflammation. Furthermore, clinical observations in patients with polycystic ovary syndrome (PCOS) demonstrated that SGLT2 inhibitors ameliorated patient anthropometric parameters, body composition and insulin resistance. Therefore, it is of importance to explore the central mechanism of SGLT2 inhibitors in the recovery of reproductive function in patients with PCOS and obesity. Here, we review the hypothalamic inflammatory mechanisms of HFD-induced microglial activation, with a focus on the clinical utility and possible mechanism of SGLT2 inhibitors in promoting reproductive fitness.

Keywords: HPO axis; SGLT2 inhibitor; high-fat diet; hypothalamic inflammation; microglia; ovulatory disorder.

Publication types

  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2* / metabolism
  • Diet, High-Fat / adverse effects
  • Female
  • Glucose / metabolism
  • Glucosides / pharmacology
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Polycystic Ovary Syndrome* / drug therapy
  • Sodium / metabolism
  • Sodium-Glucose Transporter 2 / metabolism
  • Sodium-Glucose Transporter 2 Inhibitors* / pharmacology
  • Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use


  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors
  • Glucosides
  • Hypoglycemic Agents
  • Glucose
  • Sodium