HL271, a Novel Chemical Compound Derived From Metformin, Differs From Metformin in Its Effects on the Circadian Clock and Metabolism

Biochem Biophys Res Commun. 2016 Jan 15;469(3):783-9. doi: 10.1016/j.bbrc.2015.11.069. Epub 2015 Dec 18.

Abstract

Metformin is a treatment of choice for patients with type 2 diabetes. Its action involves the phosphorylation of 5'-adenosine monophosphate activated protein kinase (AMPK), leading to inhibition of liver gluconeogenesis. The effects of a novel chemical compound derived from metformin, HL271, on molecular and physiological actions involving AMPK and rhythmically-expressed circadian clock genes were investigated. HL271 potently activated AMPK in a dose-dependent manner, and produced shortening of the circadian period and enhanced degradation of the clock genes PER2 and CRY1. Although the molecular effects of HL271 resembled those of metformin, it produced different physiological effects in mice with diet-induced obesity. HL271 did not elicit glucose-lowering or insulin-sensitizing effects, possibly because of altered regulation of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase 1. This indicated that, although HL271 acted on circadian clock machinery through a similar molecular mechanism to metformin, it differed in its systemic effect on glucose and lipid metabolite regulations.

Keywords: AMPK; Cell metabolism; Circadian clock; Gluconeogenesis; Lipid metabolites; Metformin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Circadian Clocks / drug effects*
  • Energy Metabolism / drug effects
  • Energy Metabolism / physiology
  • Hep G2 Cells
  • Humans
  • Hypoglycemic Agents
  • Lipid Metabolism / drug effects
  • Metformin / analogs & derivatives*
  • Metformin / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • NIH 3T3 Cells
  • Obesity / metabolism*
  • Structure-Activity Relationship
  • Treatment Outcome

Substances

  • Cell Cycle Proteins
  • Hypoglycemic Agents
  • Metformin
  • AMP-Activated Protein Kinases