Expression of ob mRNA and its encoded protein in rodents. Impact of nutrition and obesity.

Abstract

Energy homeostasis requires the integration of physiologic systems regulating energy intake, expenditure, and storage.Adipocytes, the primary site for energy storage and energy release in response to changing energy needs of the organism, play a key role in this process (1).In addition to their well described role in energy storage, it has been suspected for many years that adipocytes also play a more active, regulatory role in fuel ho- meostasis.Specifically, it was hypothesized that adipocytes produced a signal whose intensity is linked to the adequacy of nutrient stores.This hypothetical signal was proposed to act, directly or indirectly, at the level of the hypothalamus to regu- late nutrient intake and other processes linked to fuel homeostasis (1-4).The existence of such a closed loop "adipostat" feedback system has been supported by several lines of experimentation (for review see reference 3), including parabiosis, but a definitive molecular mediator was never identified.Recently, the "obesity" gene, mutation of which is responsible for a severe syndrome of obesity with insulin resistance in the ob/ob mouse, was identified through positional cloning (5).The gene encodes a fat-specific mRNA and a predicted protein with characteristics of a secreted protein, making it a strong candidate to be a, or the, adipostatic signal from fat (5).In this report, we present evidence that expression of ob mRNA is regulated in adipose cells or tissue of the rodent in response to diverse nutritional, pharmacologic, and disease perturbations that influence adipose cell mass.We also provide evidence that the ob protein is present as a 16-kD protein in the serum of normal mice.The circulating level of ob falls in response to starvation, is increased in several models of murine obesity, including db/db, brown adipose tissue deficient mice, and mice with monosodium glutamate (MSG)' induced obesity, and is undetectable in serum of ob/ob mice.Our results suggest that the level of expression of the ob mRNA and the circulating protein that it encodes reflect the state of energy stores in a manner consistent with the proposed role of this molecule as an adipostat. MethodsAnimals.Twoor three-month-old male Sprague-Dawley rats (CD strain), or 30-35 gram CD-1 mice were obtained from Charles River 1.