THINNER 2.0

Abstract

Obesity is a health emergency, and the weight loss achieved by the existing therapeutic options is still limited and difficult to sustain over time. While metabolic surgery is an invasive approach that encompasses several secondary effects, available pharmacological approaches like the GLP-1 receptor agonists are limited in their action (~10% weight loss after one year). Bromocriptine is a dopamine agonist approved by the Food and Drug Administration of the USA for type 2 diabetes (T2D) treatment. Although not having major effects on body weight, it has insulin-sensitizing effects, also reducing cardiovascular risk. Bromocriptine’s effects are attributed to its central actions in reducing the sympathetic tone and appetite. However, recently, the PI showed that Bromocriptine treatment in diabetic obese rats restores dopaminergic machinery in the white adipose tissue (WAT) and increases lipid catabolism. This team also showed that dopaminergic signalling is downregulated in the visceral WAT of patients with insulin resistance [PMID: 33933677]. Moreover, we have shown that sleeve gastrectomy significantly increases the levels of D1DR, D2DR, and tyrosine hydroxylase in visceral AT of obese T2D rats [PMID: 36768789]. Thus, dopaminergic machinery in white adipose tissue may be a promising therapeutic target in obesity.

Recently, the PI of this proposal has been funded with an FCT-Exploratory project (THINNER) aiming to establish the mechanisms of crosstalk between dopamine, GLP-1, and ghrelin/NPY and the development of a new therapeutic strategy based on the combination of GLP-1 receptor agonists and bromocriptine. We have already shown that GLP-1R expression in human WAT is significantly correlated with dopamine receptors and obese diabetic rats treated with the dopaminergic agonist Bromocriptine have higher levels of GLP-1R [PMID: 36768789]. On the other hand, Liraglutide treatment in diabetic rats didn’t change dopamine receptors levels in WAT, suggesting that dopamine is a master regulator of other neuroendocrine mechanisms of adipose tissue energy balance, and thus a promising therapeutic target [PMID: 36768789]. On THINNER, we have observed that ghrelin/NPY and leptin/melanocortin machinery is impaired in the WAT of patients with insulin resistance. Moreover, these receptors (GHSR-1, NPY1R, NPY2R and MCR4) were upregulated by metabolic surgery in obese diabetic rats [submitted data]. Our preliminary data shows that Bromocriptine upregulates not only GHSR-1alpha and NPY1R but also melanocortin receptors (MC4R) in the rodent WAT which are known for their lipolytic actions. Accordingly, the expression of such receptors is also correlated with dopamine receptors in human WAT. Although THINNER established the ground for this comprehensive proposal, the mechanisms of crosstalk between dopamine and other catabolism-associated pathways like melanocortin is still to be disclosed. Also, the impact of combined therapeutic approaches between bromocriptine and melanocortin modulators remains unknown but may constitute a promising therapeutic option to reduce the burden of obesity, its progression to T2D and the associated cardiovascular diseases.

The magnitude of the obesity burden worldwide makes it urgent to identify new therapeutic targets to prevent the metabolic sequelae of obesity. THINNER_2.0 will deploy a research strategy centered on peripheral dopaminergic signalling as a key regulator of metabolic function and energy expenditure mechanisms in WAT. Building upon the previous achievements, preliminary data and previous funding of the team, THNNER_2.0 will fill critical gaps in obesity treatment, designing and deploying pharmacological strategies targeted to molecular players that may be key factors in adipose tissue dys(function) and metabolic (dys)regulation [PMID: 38219974]. Combining dopaminergic agonists with modulators of the melanocortin system will simultaneously modulate two of the most important neuroendocrine systems in the adipose tissue.