The Imprinted Gene Neuronatin Is Regulated by Metabolic Status and Associated With Obesity

Abstract

Using restriction fragment differential display (RFDD) technology, we have identified the imprinted gene neuronatin (Nnat) as a hypothalamic target under the influence of leptin. Nnat mRNA expression is decreased in several key appetite regulatory hypothalamic nuclei in rodents with impaired leptin signaling and during fasting conditions. Furthermore, peripheral administration of leptin to ob/ob mice normalizes hypothalamic Nnat expression. Comparative immunohistochemical analysis of human and rat hypothalami demonstrates that NNAT protein is present in anatomically equivalent nuclei, suggesting human physiological relevance of the gene product(s). A putative role of Nnat in human energy homeostasis is further emphasized by a consistent association between single nucleotide polymorphisms (SNPs) in the human Nnat gene and severe childhood and adult obesity.

New mechanisms involved in paternal 20q disomy associated with pseudohypoparathyroidism

“…In fact, when we looked at the imprinted genes located at 20q11.2-q13.13 (those which are shared by cases 2 and 3 but not by 1 and 4), we found that some of them could explain the different phenotypes. For example, NNAT, located at 20q11.2-q12 and coding for neuronatin, an imprinted gene actively transcribed only from the paternal allele (50) and whose putative role in human energy homeostasis has been pointed out (51), could explain the macrosomic appearance in the neonatal period of case 3 and the obesity in the infant period of case 2. Besides, it is well known that genes expressed from only one allele are often involved in regulation of growth and hence indirectly in the control of energy and glucose homeostasis (52).…”

Neuronatin-mediated Aberrant Calcium Signaling and Endoplasmic Reticulum Stress Underlie Neuropathology in Lafora Disease

“…In adult mice, it is also found to be selectively expressed in various limbic structures (31) of brain and several non-neural tissues including skin (33,34). Existing literature suggests the involvement of neuronatin in the regulation of glycogen and lipid metabolism, and its mutation is associated with obesity (31,32,37,39). The primary and secondary structure of neuronatin is also strikingly similar with phospholamban (an ER-resident Ca 2ϩ regulator found in cardiac muscle), and recent reports have demonstrated that it is indeed involved in increasing the intracellular Ca 2ϩ by antagonizing SERCA2 pump in the ER (27,38).…”

“…Neuronatin is also expressed in several other peripheral tissues including pancreas, adipose tissues, and skin (32)(33)(34). Although the physiological function of neuronatin is poorly understood, existing literature indicates its involvement in glucose-mediated insulin secretion from pancreas, in adipogenesis, and in metabolic regulation (31,32,(35)(36)(37). Interestingly, neuronatin has significant homology with phospholamban and PMP1 that function as regulatory subunit of ion channel and shown to promote neural lineage in embryonic stem cells through increasing the intracellular Ca 2ϩ by antagonizing serco/endoplasmic reticulum Ca 2ϩ -ATPase-2 (SERCA2) (27,38).…”

“…It exists in two major isoforms, ␣ and ␤, consisting of 81 and 54 amino acids, respectively (29,30). In adult mice brain, it is expressed at very low levels and largely restricted to limbic structures (31). Neuronatin is also expressed in several other peripheral tissues including pancreas, adipose tissues, and skin (32)(33)(34).…”

Imprinted genes and hypothalamic function

“…Expression is downregulated after fasting and in genetic models of obesity (ob/ob mice), and is responsive to leptin administration, suggesting an involvement in regulating energy homeostasis. No knockout of Nnat has been reported, but in humans single nucleotide polymorphisms in NNAT are associated with severe childhood and adult obesity (Vrang et al 2010). Of additional imprinted genes with hypothalamic functions, Gnas and Peg3 are dealt with in detail below.…”