Figure 1.

The adipokines adiponectin and leptin have largely inhibitory effects on ceramide levels, while ceramides are known to cause myriad effects in cellular components, different cell types, and organs. Adiponectin inhibits ceramides through the intrinsic ceramidase activity of its receptors (1), AdipoR1 and AdipoR2. The mechanism of leptin’s action on ceramides remains unknown, although it has been hypothesized that leptin may exert its influence through inhibition of carnitine palmitoyltransferase-1c (CPT-1c) by malonyl-CoA (2). Conversely, ceramide accumulation may cause ER stress and subsequent leptin resistance (3–6). The previous two relationships are visualized in gray to indicate that they have not been extensively studied and characterized. Ceramides are known to act on mitochondria and cause increased mitophagy, apoptosis, and generation of reactive oxygen species (ROS), as well as decreased β-oxidation and overall oxidative capacity. Ceramides have been shown to cause mitophagy in cardiomyocytes and neurons, among others (not shown) (7). Ceramides decrease insulin sensitivity in skeletal muscle, liver, heart, and adipose (8, 9). Their accumulation may cause decreased leptin sensitivity in the brain and adipose tissue. In the vasculature, ceramide accumulation leads to increased atherosclerotic plaques and inflammatory arteriolar dilation (10–13). They can also lead to increased cardiovascular disease (14, 15), hepatic steatosis (16), and increased inflammation in immune cells (17). As opposed to other targets, skin largely benefits from increased ceramides, with increased cell differentiation and wound healing, as well as decreased senescence (18, 19). AdipoR, adiponectin receptor; CPT-1c, carnitine palmitoyltranferase 1c; CVD, cardiovascular disease; ER, endoplasmic reticulum; IL-6, interleukin-6; MIP-1, macrophage inflammatory protein 1β; ROS, reactive oxygen species; TNFα, tumor necrosis factor α.