Molecular Mechanism of the Constitutive Activation of the L250Q Human Melanocortin-4 Receptor Polymorphism †

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65471/1/j.1747-0285.2006.00362.x.pd

The role of the central melanocortin system in the regulation of food intake and energy homeostasis: lessons from mouse models

A little more than a decade ago, the molecular basis of the lipostat was largely unknown. At that time, many laboratories were at work attempting to clone the genes encoding the obesity, diabetes, fatty, tubby and agouti loci, with the hope that identification of these obesity genes would help shed light on the process of energy homeostasis, appetite and energy expenditure. Characterization of obesity and diabetes elucidated the nature of the adipostatic hormone leptin and its receptor, respectively, while cloning of the agouti gene eventually led to the identification and characterization of one of the key neural systems upon which leptin acts to regulate intake and expenditure. In this review, we describe the neural circuitry known as the central melanocortin system and discuss the current understanding of its role in feeding and other processes involved in energy homeostasis

Expression studies of pigmentation and POU-domain genes in human melanoma cells

Human melanoma cell lines have been used to examine the regulation of the tyrosinase (TYR) and tyrosinase-related protein genes TRP-1 and TRP-2 in response to differentiating chemicals and UV irradiation. TRP-1 mRNA levels can be repressed by treatment with the differentiating chemicals DMSO and HMBA. There is little effect of UV irradiation on pigment synthesis by human melanoma cell lines or tyrosinase activity, with variable effects on the levels of the TYR, TRP-1, and TRP-2 gene transcripts. The human TRP-1 gene promoter has been isolated and its activity tested by transient cell transfection to begin an examination of signal transduction mechanisms operating in response to pigmenting and differentiating agents. To identify transcription factors that may be involved in melanocytic gene expression, we studied the N-Oct-3 and N-Oct-5 octamer-binding activities normally expressed in the neuroectodermal cell lineage and which are expressed at high levels in melanoma cells. POU-domain-containing cDNA have been isolated from the A2058 human melanoma cell line that are homologous to the brn-2 gene that encodes N-Oct-3 and N-Oct-5

Integrative capacity of the caudal brainstem in the control of food intake

The caudal brainstem nucleus of the solitary tract (NTS) is the initial central nervous system (CNS) terminus for a variety of gastrointestinal mechanical, nutrient chemical and gut peptide signals that limit the amount of food consumed during a meal. It receives neuroanatomical projections from gut vagal and non-vagal visceral afferents that mediate the CNS representation of these meal-stimulated gut feedback signals, and is reciprocally connected to a range of hypothalamic and limbic system sites that play significant roles in the neural processing of meal-related stimuli and in determining food consumption. Neurons in the NTS also contains elements of leptinergic and melanocortinergic signalling systems, presenting the possibility that the brainstem actions of these neuropeptides affect both the NTS processing of meal-stimulated gut afferent neural activity and its behavioural potency. Taken together, these features suggest that the NTS is ideally situated to integrate central and peripheral signals that determine meal size. This manuscript will review recent support from molecular genetic, neurophysiological and immunocytochemical studies that begin to identify and characterize the types of integrative functions performed within the NTS, and highlight the extent to which they are consistent with a causal role for NTS integration of peripheral gut and central neuropeptide signals important in the control of food intake