Adiponectin, the adiponectin paradox, and Alzheimer's Disease: Is this association biologically plausible?

Dementia, especially Alzheimer's Disease (AD) and vascular dementia, is a major public health problem that continues to expand in both economically emerging and hegemonic countries. In 2017, the World Alzheimer Report estimated that over 50 million people were living with dementia globally. Metabolic dysfunctions of brain structures such as the hippocampus and cerebral cortex have been implicated as risk factors for dementia. Several well-defined metabolic risk factors for AD include visceral obesity, chronic inflammation, peripheral and brain insulin resistance, type 2 diabetes mellitus (T2DM), hypercholesterolemia, and others. In this review, we describe the relationship between the dysmetabolic mechanisms, although still unknown, and dementia, particularly AD. Adiponectin (ADPN), the most abundant circulating adipocytokine, acts as a protagonist in the metabolic dysfunction associated with AD, with unexpected and intriguing dual biological functions. This contradictory role of ADPN has been termed the adiponectin paradox. Some evidence suggests that the adiponectin paradox is important in amyloidogenic evolvability in AD. We present cumulative evidence showing that AD and T2DM share many common features. We also review the mechanistic pathways involving brain insulin resistance. We discuss the importance of the evolvability of amyloidogenic proteins (APs), defined as the capacity of a system for adaptive evolution. Finally, we describe potential therapeutic strategies in AD, based on the adiponectin paradox.

Insights Into the Controversial Aspects of Adiponectin in Cardiometabolic Disorders.

In 2016, the World Health Organization estimated that more than 1.9 billion adults were overweight or obese. This impressive number shows that weight excess is pandemic. Overweight and obesity are closely associated with a high risk of comorbidities, such as insulin resistance and its most important outcomes, including metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. Adiponectin has emerged as a salutary adipocytokine, with insulin-sensitizing, anti-inflammatory, and cardiovascular protective properties. However, under metabolically unfavorable conditions, visceral adipose tissue-derived inflammatory cytokines might reduce the transcription of the adiponectin gene and consequently its circulating levels. Low circulating levels of adiponectin are negatively associated with various conditions, such as insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular disease. In contrast, several recent clinical trials and meta-analyses have reported high circulating adiponectin levels positively associated with cardiovascular mortality and all-cause mortality. These results are biologically intriguing and counterintuitive, and came to be termed "the adiponectin paradox". Adiponectin paradox is frequently associated with adiponectin resistance, a concept related with the downregulation of adiponectin receptors in insulin-resistant states. We review this contradiction between the apparent role of adiponectin as a health promoter and the recent evidence from Mendelian randomization studies indicating that circulating adiponectin levels are an unexpected predictor of increased morbidity and mortality rates in several clinical conditions. We also critically review the therapeutic perspective of synthetic peptide adiponectin receptors agonist that has been postulated as a promising alternative for the treatment of metabolic syndrome and type 2 diabetes mellitus.