Elsevier

Experimental Gerontology

Volume 44, Issues 1–2, January–February 2009, Pages 20-25
Experimental Gerontology

Changes in the neuroendocrine control of energy homeostasis by adiposity signals during aging

https://doi.org/10.1016/j.exger.2008.05.005Get rights and content

Abstract

Energy balance in mammals is modulated by peripheral signals that inform the brain about the magnitude of fat stores, the amount of food in the gastrointestinal tract, and the level of nutrients such as glucose in the circulation. Among these, insulin and leptin are considered adiposity signals involved in the long-term maintenance of fat stores. Here we review the mechanisms of action of leptin and insulin in the hypothalamus and how these mechanisms are altered during aging in rat models. Aged rats are characterized by increased fat mass, central leptin and insulin resistance, and hyperleptinemia. Leptin resistance is manifested by its failure to inhibit food intake, deplete fat stores, down regulate its own expression in adipose tissue, and increase energy expenditure. Moreover, leptin and insulin signaling are decreased in hypothalamus from aged rats. Calorie restriction and fasting studies provide controversial data on the cause–effect interrelationship between increased adiposity and development of central leptin resistance. Although in the absence of obesity leptin resistance seems to be a characteristic of aged animals, adiposity could either reinforce it or cause an early onset of this resistance. More studies are necessary to clarify the role of the hypothalamus in the development of age-associated obesity and insulin resistance.

Introduction

Neuroendocrine regulation of energy homeostasis involves cross-talk between the periphery and the CNS. Several peptidic factors, mainly originating in the periphery, interact with specific brain targets such as hypothalamic nuclei or transmit their signal through the vagus nerve and sympathetic fibers, which activate neurons in another brain area, the nucleus of the tractus solitarius (NTS). Thus, hypothalamus and NTS seem to play a key role integrating peripheral signals and generating homeostatic responses, transmitted by the autonomic nervous system which regulate food intake and energy expenditure (Badman and Flier, 2005, Takahasi, 2003).

Peripheral signals regulating energy homeostasis can be classified into one of the three following types: (1) long-term energy balance signals, such as leptin and insulin which act as adiposity signals indicating the amount of fat stored in the organism (Schwartz et al., 2000, Spiegelman and Flier, 2001); (2) hunger and satiety signals, such as ghrelin, glucagon-like peptide 1 (GLP-1) or cholecystokinin (CCK) among others, which regulate the short-term eating behavior (Badman and Flier, 2005, Stanley et al., 2005); and (3) nutrient signals, such as glucose or fatty acids, which reflect the whole-body nutrient status and can modulate appetite, body weight and liver metabolism (Hu et al., 2003, Obici et al., 2003). The first and the last types of signals act mainly through activation of hypothalamic neurons, whereas hunger and satiety signals target additionally to the NTS and other brainstem areas. In addition to these signals, other factors currently under study, such as adiponectin or resistin, seem to have an effect on energy balance acting either centrally on hypothalamus, or peripherally modulating energy metabolism of several tissues. Moreover, it should be pointed out that most of the hormonal factors mentioned above, in addition to their central targets, can modulate peripheral tissues via endocrine and paracrine action.

In this review we examine the role of the long-term modulators of energy balance, leptin and insulin, with special emphasis in the changes that occur during aging in their respective effects on food intake and energy expenditure.

Section snippets

Lipostatic theory: leptin and insulin as adiposity signals

The original lipostatic hypothesis of Kennedy aimed to understand how the brain can monitor the status of fat stores in the organism and proposed the existence of a humoral factor circulating in proportion to the magnitude of these stores. This factor would interact with specific areas in the CNS involved in the regulation of energy homeostasis, closing a classical feed-back loop. Insulin was the first factor so far described that met the criteria to be considered as an “adiposity signal”: its

Effect of aging on physiological leptin action

Changes in leptin action with aging have been mainly investigated in rat models. Common features of humans and rat models of aging are the increase in body weight, the accretion of fat mass and the development of hyperleptinemia. This last characteristic is also observed in most obese animals and humans and could be the consequence of central leptin resistance. Thus, it can be postulated that aging is associated with the failure of leptin to regulate fat stores that increase up to the beginning

Effect of aging on hypothalamic leptin signaling

Both, in F344xBN and Wistar rats, it has been demonstrated that 24-month-old animals show a lower presence of Ob-Rb leptin receptors in the hypothalamus (Fernández-Galaz et al., 2001, Fernández-Galaz et al., 2002, Scarpace et al., 2001). In Wistar rats this decrease is not observed in 8-month-old rats, despite the fact that these animals show already elevated leptin levels and an adiposity index similar to that observed in 24-month-old rats. (Scarpace et al., 2001) have studied the

Effect of aging on central insulin action and signaling

To the best of our knowledge we have reported the unique study on aging-associated changes in central insulin action (García-San Frutos et al., 2007). Using two different doses of centrally infused insulin for 7 days we demonstrated that it causes a dose-dependent decrease in daily food intake and body weight, and these effects were blunted in 8 and 24-month-old rats. The fact that the beginning of the attenuation of central insulin response concurs with the major increase in adiposity index (

Summary and perspective

Leptin, together with insulin, seems to serve as sensor of available fuels and by interacting with its hypothalamic targets modulates changes in eating behavior and sympathetic outflow that decrease food intake and increase energy expenditure. The available data in rodents and humans indicate that during aging the serum leptin concentration increases, leptin resistance develops, and there is a progressive increment of fat mass and visceral adiposity. A major unanswered question refers to the

Acknowledgements

The work of author’s laboratories has been supported by grants BFU2005-7647-C03 from Ministerio de Eduación y Ciencia (Spain), PCI-08-0136 and CS-04-001 from Junta de Comunidades de Castilla-La Mancha (Spain) and by Fundación Mutua Madrileña. The CBMSO is the recipient of institutional aid from the Ramón Areces Foundation.

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