Nicotine Acutely Induces Hyperglycemia and Hepatic Steatosis by Altering the Sympathetic Outflow

Cigarette smoking is a major risk factor for cardiovascular diseases, cancers, and metabolic syndrome. Studies have shown that smoking induces insulin resistance and hyperglycemia. Nicotine, the major constituent of cigarette, is thought to be responsible for the impaired insulin sensitivity and glycemic control. However, the underlying mechanisms are poorly understood. To first examine the acute effects of nicotine on glucose metabolism, we injected chow‐fed mice with either saline or nicotine (1.5mg/kg) intraperitoneally. Interestingly, a single injection of nicotine increased blood glucose by 50% within the first 15 min that lasted at least for 1h. Further, treatment with nicotine led to impaired glucose tolerance compared to controls. Lipolysis from white adipose tissue (WAT), primarily driven by the sympathetic nervous system (SNS), can provide glucogenic substrates to liver to promote gluconeogenesis. However, mice unable to mobilize lipids from WAT due to lack of adipose‐specific adipose triglyceride lipase (ATGL) similarly elevated blood glucose following nicotine injection. On the other hand, deletion of tyrosine hydroxylase (the rate‐limiting enzyme for catecholamine synthesis) only in the periphery completely abolished the rise of glucose in nicotine group, suggesting that the sympathetic drive to peripheral organs other than WAT may be responsible for nicotine‐induced hyperglycemia. Indeed, nicotine injection increased the sympathetic outflow to liver by 20%, but not WAT, as measured by norepinephrine (NE) concentrations 1h after injection. Hepatic glycogen content was markedly reduced in nicotine‐treated animals, probably due to the SNS‐driven glycogenolysis in liver. Surprisingly, a single nicotine injection in high‐fat (HF)‐fed obese mice not only induced severe hyperglycemia, but also hepatic steatosis compared to saline‐treated HF controls. NE content in liver was significantly lower (>two‐fold) in nicotine‐treated HF group compared to HF control group. While the reasons are not clear, we speculate that unlike in chow‐fed mice, nicotine in HF‐fed mice may suppress the sympathetic drive to liver resulting in less beta oxidation and/or reduced triglyceride secretion, hence fatty liver, whereas it may raise the sympathetic outflow to WAT to increase lipolysis that in turn can promote hepatic gluconeogenesis, resulting in hyperglycemia. Support or Funding Information NIH K01 DK099463Presidents' Collaborative Research Initiative Grant, Texas Tech University System This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .