Neuropeptide Y and agouti-related peptide mediate complementary functions of hyperphagia and reduced energy expenditure in leptin receptor deficiency

Abstract

Neuropeptide Y (NPY) and agouti-related peptide (AGRP) can produce hyperphagia, reduce energy expenditure, and promote triglyceride deposition in adipose depots. As these two neuropeptides are coexpressed within the hypothalamic arcuate nucleus and mediate a major portion of the obesity caused by leptin signaling deficiency, we sought to determine whether the two neuropeptides mediated identical or complementary actions. Because of separate neuropeptide receptors and signal transduction mechanisms, there is a possibility of distinct encoding systems for the feeding and energy expenditure aspects of leptin-regulated metabolism. We have genetically added NPY deficiency and/or AGRP deficiency to LEPR deficiency isolated to AGRP cells. Our results indicate that the obesity of LEPR deficiency in AGRP/NPY neurons can produce obesity with either AGRP or NPY alone with AGRP producing hyperphagia while NPY promotes reduced energy expenditure. The absence of both NPY and AGRP prevents the development of obesity attributable to isolated LEPR deficiency in AGRP/NPY neurons. Operant behavioral testing indicated that there were no alterations in the reward for a food pellet from the AGRP-specific LEPR deficiency.

Fig. 1.

Twenty-four-hour metabolic characteristics of mice lacking Lepr in AGRP/NPY neurons and lacking AGRP. The data are presented over a 24-h period with data collected over 5 d. A, Twenty-four-hour oxygen consumption of Agrp KO AGRP:Lepr^−/− and Agrp KO Lepr-flox/flox female mice. The Agrp KO AGRP:Lepr^−/− mice showed a decrease in VO₂ between 1400 h and 1800 h, compared with Agrp KO Lepr-flox/flox mice (P < 0.05 for hourly time bins, signified with asterisks). B, Twenty-four-hour carbon dioxide production of Agrp KO AGRP:Lepr^−/− and Agrp KO Lepr-flox/flox female mice. The Agrp KO AGRP:Lepr^−/− mice showed a decrease in VCO₂ between 0800 h and 0900 h, 1400 h and 1800 h, compared with Agrp KO Lepr-flox/flox mice (P < 0.05 for hourly time bins, signified with asterisks). C. Respiratory exchange ratios of Agrp KO AGRP:Lepr^−/− and Agrp KO Lepr-flox/flox female mice. There was no significant difference in the RERs of the two groups of mice.