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Intercrosses of heterozygous pro-opiomelanocortin (POMC) mice result in homozygous null progeny at lower frequencies than expected. Genotyping offspring at pre-, peri-, and postnatal stages revealed that over half of homozygous null mutants die in the early postnatal stages. To investigate the reasons for this early postnatal lethality, we analyzed in detail different parameters in the initial hours after birth. POMC null mutants born to heterozygous dams presented at birth with corticosterone levels no different from wildtype littermates, were euglycemic, and had normal liver glycogen stores. However, already 30 min after birth corticosterone levels dropped by 80% and were undetectable thereafter, while corticosterone levels in wildtype animals increased during postnatal hours. Circulating adrenaline was almost below detection 1h after birth. Blood glucose levels fell sharply in all genotypes within 30 min after birth; however, wildtype and heterozygous pups overcame hypoglycemia within an hour, while mutant pups stayed hypoglycemic. The depletion of liver glycogen stores in mutant pups was significantly less efficient compared to their littermates in the hours after birth. POMC null mutant mice born to POMC null mutant dams completely lack corticosterone and die of the expected respiratory dysfunction. In contrast, POMC null mutant mice born to heterozygous dams do not die of respiratory problems, but rather due to hypoglycemia. Our studies confirm an essential involvement of POMC peptides and of adrenal glucocorticoids and catecholamines on glucose homeostasis critical for early postnatal survival., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Pro-opiomelanocortin (POMC) is a prohormone which undergoes extensive tissue and cell specific post-translational processing producing a number of active peptides with diverse biological roles ranging from control of adrenal function to pigmentation to the regulation of feeding. One approach to unraveling the complexities of the POMC system is to engineer mouse mutants which lack specific POMC peptides. We describe here the design, generation, validation, and preliminary analysis of one such partial POMC mutant specifically lacking α-MSH. In contrast to POMC null mutant mice, mice lacking α-MSH in the presence of all other POMC peptides maintain adrenal structures and produce corticosterone comparable to wildtype littermates; however, they still have decreased levels of aldosterone, as found in POMC null mutant mice. Our findings demonstrate that α-MSH is not needed for maintenance of adrenal structure or for corticosterone production, but is needed for aldosterone production. These data demonstrate that mouse strains generated with precise genetic modifications of POMC peptide processing can answer questions about POMC peptide function. Further analysis of this and additional strains of mice with modified POMC peptide processing patterns will open up a novel avenue for studying the roles of individual POMC peptides., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The adrenal gland regulates a number of essential biological functions through production of steroids and catecholamines. Pro-opiomelanocortin (POMC)-derived peptides have been implicated in all aspects of generating, maintaining, and functioning of the adrenal glands. An appreciation for the roles of POMC-derived peptides with respect to the adrenal has been gained from experiments in vitro, and in vivo in different animal models which surgically, pharmacologically, or genetically decrease or increase the amount of POMC peptides available. We recently produced a mouse model with a deletion of the entire coding region of the POMC gene, thus lacking all POMC-derived peptides, from all sources, and at all times. Here we will summarize and discuss the results of traditional in vivo studies on the role of POMC peptides in adrenal development, maintenance, and function in the context of findings in a mouse model genetically lacking all POMC-derived peptides.