Harnessing the Power of Leptin: The Biochemical Link Connecting Obesity, Diabetes, and Cognitive Decline

Abstract

In this review, the current understanding of leptin's role in energy balance, glycemic regulation, and cognitive function is examined, and its involvement in maintaining the homeostatic "harmony" of these physiologies is explored. The effects of exercise on circulating leptin levels are summarized, and the results of clinical application of leptin to metabolic disease and neurologic dysfunction are reviewed. Finally, pre-clinical evidence is presented which suggests that synthetic peptide leptin mimetics may be useful in resolving not only the leptin resistance associated with common obesity and other elements of metabolic syndrome, but also the peripheral insulin resistance characterizing type 2 diabetes mellitus, and the central insulin resistance associated with certain neurologic deficits in humans.

Keywords: cognitive function; diabetes; exercise; leptin mimetics; obesity; synthetic peptides.

FIGURE 1

Leptin: the biochemical link connecting obesity, diabetes, and cognitive decline. Leptin deficiency (hypoleptinemia) and leptin resistance (hyperleptinemia) are characterized by dysfunctional leptin signaling both centrally and in the periphery. In the brain, dysfunctional leptin signaling in the hypothalamus causes numerous systemic metabolic defects including, but not limited to obesity and diabetes (insulin resistance). Dysfunctional leptin signaling in the hippocampus and cerebral cortex results in the induction and progression of the beta amyloid (Aβ) and Tau pathology associated with Alzheimer’s Disease (AD) and other forms of dementia. Obesity and diabetes are considered significant risk factors for the onset and progression of AD and AD-like cognitive impairment.