Obesity Paradox and Smoking Gun: A Mystery of Statistical Confounding?

Abstract

The obesity paradox is a term coined for human conditions in which obesity is associated with a lower mortality than being underweight (i.e., body below normal or healthy body weight). Smoking is often cited as a key cofounder of obesity paradox but how smoking causes obesity paradox is unknown. Here we highlight that the obesity paradox can be attributed to insulin resistance and aberrant lipolysis in cardiovascular diseases.

Keywords: body weight; humans; insulin resistance; lipolysis; nicotine.

Figure

Schematic representation of the role of cigarette smoking-induced IR in the obesity paradox. First, nicotine-enhanced lipolysis by sympathetic nervous system activation contributes to IR and body weight loss. Second, nicotine acts via adipocyte α7nAchR to induce ROS and activate AMPKα2. This subsequently enhances MKP1 degradation, resulting in IRS1 reduction and IR. Third, nicotine induces IR via mTOR activation in the skeletal muscle. Hence, nicotine promotes both body weight loss and IR-induced cardiovascular diseases, which may underlie the so-called obesity paradox. →, induce or act on; ↑, increase; ↓, decrease. Other abbreviations are defined in the main text.