Dopamine D2 receptor upregulates leptin and IL-6 in adipocytes

Wang, Xiaoyan; Villar, Van Anthony M.; Tiu, Andrew; Upadhyay, Kiran; Cuevas, Santiago

doi:10.1194/jlr.m081000

Cited by 23 publications

(17 citation statements)

References 41 publications

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“…These data suggest that bromocriptine achieves its metabolic effects in part by targeting peripheral catecholamine receptors in addition to those in the pancreas. Consistent with this, D2R is expressed in adipose tissue and D2R-mediated signaling regulates adipokine expression (Borcherding et al, 2011;Freyberg et al, 2017;Wang et al, 2018).…”

Section: Discussionmentioning

confidence: 82%

Dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptine

et al. 2022

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Section: Discussionmentioning

confidence: 82%

Dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptine

et al. 2022

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“…As WT- and R6/2 females with 79Q overexpression showed distinct metabolic phenotypes at 11 weeks post-injection (weight gain and weight loss respectively), with a shared feature of increased adiposity and downregulation of B3AR and ATGL, key mediators of lipolysis [ 45 , 46 ], we next established expression profiles of hypothalamic targets with suggested central roles in obesity and modulation of adipose tissue, including oxytocin [ 47 , 48 ], orexin [ 49 , 50 ], pro-opiomelanocortin (POMC) [ 51 , 52 ], brain-derived neurotrophic factor (BDNF) [ 53 ] and dopamine receptor D2 (DRD2) [ 54 , 55 ]. These markers are also known to be selectively altered in HD patients and mouse models [ 15 , 21 , 56 ].…”

Section: Resultsmentioning

confidence: 99%

Hypothalamic expression of huntingtin causes distinct metabolic changes in Huntington's disease mice

Dickson

Soylu-Kucharz

Petersén

et al. 2022

Molecular Metabolism

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Objective In Huntington's disease (HD), the disease-causing huntingtin (HTT) protein is ubiquitously expressed and causes both central and peripheral pathology. In clinical HD, a higher body mass index has been associated with slower disease progression, indicating the role of metabolic changes in disease pathogenesis. Underlying mechanisms of metabolic changes in HD remain poorly understood, but recent studies suggest the involvement of hypothalamic dysfunction. The present study aimed to investigate whether modulation of hypothalamic HTT levels would affect metabolic phenotype and disease features in HD using mouse models. Methods We used the R6/2 and BACHD mouse models that express different lengths of mutant HTT to develop lean- and obese phenotypes, respectively. We utilized adeno-associated viral vectors to overexpress either mutant or wild-type HTT in the hypothalamus of R6/2, BACHD, and their wild-type littermates. The metabolic phenotype was assessed by body weight measurements over time and body composition analysis using dual-energy x-ray absorptiometry at the endpoint. R6/2 mice were further characterized using behavioral analyses, including rotarod, nesting-, and hindlimb clasping tests during early- and late-time points of disease progression. Finally, gene expression analysis was performed in R6/2 mice and wild-type littermates in order to assess transcriptional changes in the hypothalamus and adipose tissue. Results Hypothalamic overexpression of mutant HTT induced significant gender-affected body weight gain in all models, including wild-type mice. In R6/2 females, early weight gain shifted to weight loss during the corresponding late stage of disease despite increased fat accumulation. Body weight changes were accompanied by behavioral alterations. During the period of early weight gain, R6/2 mice displayed a comparable locomotor capacity to wild-type mice. When assessing behavior just prior to weight loss onset in R6/2 mice, decreased locomotor performance was observed in R6/2 females with hypothalamic overexpression of mutant HTT. Transcriptional downregulation of beta-3 adrenergic receptor (B3AR), adipose triglyceride lipase (ATGL), and peroxisome proliferator-activated receptor-gamma (PPAR γ ) in gonadal white adipose tissue was accompanied by distinct alterations in hypothalamic gene expression profiles in R6/2 females after mutant HTT overexpression. No significant effect on metabolic phenotype in R6/2 was seen in response to wild-type HTT overexpression. Conclusions Taken together, our findings provide further support for the role of HTT in metabolic control via hypothalamic neurocircuits. Understanding the specific central neurocircuits and their peripheral link underlying metabolic imbalance in HD may open up avenues for novel therapeutic interventions.

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“…An increase in leptin, combined with a transient increase in insulin resistance has been suggested to be responsible for the earlier onset of puberty in children with higher body fat (96). In addition, leptin plays a role in regulating inflammation in fat cells (97,98), and this process may be further modulated by dopamine expression (99,100). Given the complex interactions among dopamine, inflammation, and adipocyte-releasing hormones, future work will be needed to disentangle the contributions of these signals on neuroinflammation within dopaminergic pathways and their role in unhealthy eating and weight gain in children.…”

Section: Discussionmentioning

confidence: 99%

Nucleus accumbens cytoarchitecture predicts weight gain in children

Rapuano

Laurent

Hagler

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The prevalence of obesity in children and adolescents worldwide has quadrupled since 1975 and is a key predictor of obesity later in life. Previous work has consistently observed relationships between macroscale measures of reward-related brain regions (e.g., the nucleus accumbens [NAcc]) and unhealthy eating behaviors and outcomes; however, the mechanisms underlying these associations remain unclear. Recent work has highlighted a potential role of neuroinflammation in the NAcc in animal models of diet-induced obesity. Here, we leverage a diffusion MRI technique, restriction spectrum imaging, to probe the microstructure (cellular density) of subcortical brain regions. More specifically, we test the hypothesis that the cell density of reward-related regions is associated with obesity-related metrics and early weight gain. In a large cohort of nine- and ten-year-olds enrolled in the Adolescent Brain Cognitive Development (ABCD) study, we demonstrate that cellular density in the NAcc is related to individual differences in waist circumference at baseline and is predictive of increases in waist circumference after 1 y. These findings suggest a neurobiological mechanism for pediatric obesity consistent with rodent work showing that high saturated fat diets increase gliosis and neuroinflammation in reward-related brain regions, which in turn lead to further unhealthy eating and obesity.

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Dopamine D2 receptor upregulates leptin and IL-6 in adipocytes

Abstract: Leptin is a pro-inflammatory cytokine secreted by the adipose tissue.

Cited by 23 publications

References 41 publications

Dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptine

Dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptine

Hypothalamic expression of huntingtin causes distinct metabolic changes in Huntington's disease mice

Nucleus accumbens cytoarchitecture predicts weight gain in children

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