**3. Adiponectin as a Modulator of Metabolic Disorder**

Adiponectin is secreted with the bioactive molecule leptin from normal adipose tissues (together, they are called adipokines) [35]. It regulates glucose and fatty acid metabolism by increasing insulin sensitivity of peripheral organs [36–38]. However, small amounts of adiponectin, an adipose-tissuespecific protein, can also be synthesized by other cell types. Paradoxically, the adiponectin level decreases with the increase of central adiposity, which causes obesity [39–41]. Obesity causes damage to several organ systems because it regulates MetS, which can be characterized physiologically as excess weight and pathologically as high triglyceride levels and insulin resistance [42]. Moreover, obesity is related to an increase in cognitive decline and AD [43]. Recently, our laboratory has shown that touchscreen-based behavioral testing of high-fat diet mice led to an impairment in cognitive function compared with cognitive function in normal diet mice [44]. MetS, including obesity, cardiovascular disease, type 2 diabetes, and neurodegenerative disorders, is associated with the regulation of adiponectin expression [8,45,46]. Like other hormonal proteins, adiponectin also functions through specific receptors known as adiponectin receptors. Adiponectin receptors have been classified into adiponectin receptor (AdipoR) 1, AdipoR2, and T-cadherin. Through the recruitment of adaptor protein APPL1 by AdipoRs activation, adiponectin signaling regulates a series of signaling pathways [47]. AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-α (PPARα), IkB kinase (IKK)/NF-κB/PTEN, IRS1/2–Akt, and Ras-ERK1/2 signaling are examples of downstream adiponectin signaling [48–52]. Adiponectin receptors are found to be expressed throughout the whole brain. Thundyil et al. suggested that in the cortical neurons, AdipoR1 expression is more prominent than AdipoR2 expression [53]. On the other hand, T-cadherin acts as the coreceptor of a unidentified receptor, through which the adiponectin can transmit the metabolic signals [54].
