Relationship of Dopamine Type 2 Receptor Binding Potential With Fasting Neuroendocrine Hormones and Insulin Sensitivity in Human Obesity

Abstract

OBJECTIVEMidbrain dopamine (DA) neurons, which are involved with reward and motivation, are modulated by hormones that regulate food intake (insulin, leptin, and acyl ghrelin [AG]). We hypothesized that these hormones are associated with deficits in DA signaling in obesity.RESEARCH DESIGN AND METHODSWe assessed the relationships between fasting levels of insulin and leptin, and AG, BMI, and insulin sensitivity index (SI) with the availability of central DA type 2 receptor (D2R). We measured D2R availability using positron emission tomography and [18F]fallypride (radioligand that competes with endogenous DA) in lean (n = 8) and obese (n = 14) females. Fasting hormones were collected prior to scanning and SI was determined by modified oral glucose tolerance test.RESULTSParametric image analyses revealed associations between each metabolic measure and D2R. The most extensive findings were negative associations of AG with clusters involving the striatum and inferior temporal cortices. Regional regression analyses also found extensive negative relationships between AG and D2R in the caudate, putamen, ventral striatum (VS), amygdala, and temporal lobes. SI was negatively associated with D2R in the VS, while insulin was not. In the caudate, BMI and leptin were positively associated with D2R availability. The direction of associations of leptin and AG with D2R availability are consistent with their opposite effects on DA levels (decreasing and increasing, respectively). After adjusting for BMI, AG maintained a significant relationship in the VS. We hypothesize that the increased D2R availability in obese subjects reflects relatively reduced DA levels competing with the radioligand.CONCLUSIONSOur findings provide evidence for an association between the neuroendocrine hormones and DA brain signaling in obese females.

Bromocriptine-QR therapy for the management of type 2 diabetes mellitus: developmental basis and therapeutic profile summary

“…That is to say, it is the brain's response to the environment, more so that the environment itself, that dictates the full metabolic outcome of environmental changes such as the presentation of the westernized diet. The neurophysiological literature is now replete with studies demonstrating the important roles of several neural circuits that impact peripheral fuel metabolism (reviewed in [32]) including hypothalamic arcuate-alpha melanocortin-stimulating hormone (αMSH) [33][34][35] and arcuate neuropeptide Y (NPY) -paraventricular nuclei (PVN) circuits [36][37][38], the lateral hypothalamic (LH) leptinorexin mesolimbic circuit [39][40][41][42], ventromedial hypothalamic and arcuate leptin autonomic/neuroendocrine circuits [43][44][45][46][47], and the insulin arcuate [48] and dopamine mesolimbic circuits [49,50] to name just a few. Emerging experimental evidence suggests important roles for the biological clock system residing within and around the SCN of the hypothalamus in the integration of these CNS circuits to create an orchestrated organized CNS output signal (program) to the peripheral organs respecting fuel metabolism (see discussion below) [51][52][53][54].…”

“…Dopamine also functions to inhibit feeding in the perifornical area of the hypothalamus and to inhibit sympathetic nervous system (SNS) activation via its actions at the PVN [52,123]. Moreover, positron emission topography scan studies with radiolabeled dopaminergic receptor ligands in humans have identified a decreased dopaminergic function in obese and insulinresistant individuals [49,50]. However, our recent studies suggest that these non-SCN CNS functions of dopamine that collectively tend to maintain the lean/insulin-sensitive state are actually regulated in part by circadian SNC output signals that, as described herein, are modulated by circadian dopaminergic input signals to the SCN.…”

Type 2 diabetes mellitus, drug addiction, bipolar disorder and epilepsy display overlapping aetiopathogenic mechanisms: Implication for prevention and pharmacotherapy

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“…Nos EUA, as taxas de sobrepeso e obesidade estão em constante aumento, com cerca de 35% da população adulta de ambos os sexos obesa, enquanto a taxa em adolescentes e crianças obesos chega até 15 a 30% 36 . Isso pôde ser evidenciado no fato de a maioria dos estudos (12 dos 17) ter sido conduzida nos EUA [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] .…”

“…Resultado diferente foi encontrado em um estudo conduzido nos EUA: correlação positiva entre a disponibilidade de DRD2 e IMC 34 . A justificativa encontrada pelos autores para este achado diz respeito ao horário em que o estudo foi conduzido.…”