Dopamine D2 receptor antagonist counteracts hyperglycemia and insulin resistance in diet-induced obese male mice

• DOI: 10.1371/journal.pone.0301496
• Publication Date: 2024-04-18T17:55:11Z
• Authors: Dina I. Vázquez-C...; Ana Luisa Ocampo-...; Arelí Báez-Meza; Gabriela Ramírez-...; Elva Adán-Castro; José Fernando Gar...; José Luis Dena-Be...; Ericka A. de los ...; Magdalena Karina ...; María Georgina Ortiz; Gonzalo Martínez ...; Carmen Clapp; Yazmín Macotela
• Keywords: Male; Receptors, Prolactin; Physiology; Science; Mice, Obese; Adipose tissue; Brown Adipose Tissue Function and Physiology; Diet, High-Fat; Mice; Endocrinology; Biochemistry, Genetics and Molecular Biology; Health Sciences; Humans; Animals; Insulin; Obesity; Molecular Biology; Internal medicine; Biology; Adipocyte; Metabolic Regulation; Endocrine and Autonomic Systems; Q; Insulin Signaling; R; Antagonist; Life Sciences; Insulin resistance; Hypertrophy; Role of AMP-Activated Protein Kinase in Cellular Metabolism; Hormone; Rats; Prolactin; Dopamine D2 Receptor Antagonists; Diabetes Mellitus, Type 2; Hyperglycemia; FOS: Biological sciences; Medicine; Neuroendocrine Regulation of Appetite and Body Weight; Insulin Resistance; Sulpiride; GLUT4; Research Article; Neuroscience; Receptor

Obesity leads to insulin resistance (IR) and type 2 diabetes. In humans, low levels of the hormone prolactin (PRL) correlate with IR, adipose tissue (AT) dysfunction, and increased prevalence of T2D. In obese rats, PRL treatment promotes insulin sensitivity and reduces visceral AT adipocyte hypertrophy. Here, we tested whether elevating PRL levels with the prokinetic and antipsychotic drug sulpiride, an antagonist of dopamine D2 receptors, improves metabolism in high fat diet (HFD)-induced obese male mice. Sulpiride treatment (30 days) reduced hyperglycemia, IR, and the serum and pancreatic levels of triglycerides in obese mice, reduced visceral and subcutaneous AT adipocyte hypertrophy, normalized markers of visceral AT function (PRL receptor, Glut4, insulin receptor and Hif-1α), and increased glycogen stores in skeletal muscle. However, the effects of sulpiride reducing hyperglycemia were also observed in obese prolactin receptor null mice. We conclude that sulpiride reduces obesity-induced hyperglycemia by mechanisms that are independent of prolactin/prolactin receptor activity. These findings support the therapeutic potential of sulpiride against metabolic dysfunction in obesity.