Leptin resistance and the response to positive energy balance

Abstract

Animals readily reduce food intake and normalize body weight following a period of involuntary overfeeding, suggesting that regulatory systems are engaged to defend against excess weight gain. However, these data exist in the background of an ongoing obesity epidemic, where the ready availability of palatable, energy dense foods often leads to obesity. Currently we know very little about the mechanisms underlying the normalization of body weight following involuntary overfeeding, nor do we fully understand why select individuals successfully remain lean despite living in an obesigenic environment. Recent progress in the study of leptin signaling indicates that manipulations which enhance leptin sensitivity reduce food intake and attenuate diet-induced obesity, while reductions in leptin signaling predispose to obesity. While it remains unclear whether a failure or insufficiency in the weight regulatory system contributes to obesity, this work highlights the importance of this system for the regulation of body weight and its potential value for the treatment of obesity. Nonetheless, it is necessary to more clearly identify those mechanisms that protect lean individuals from weight gain and mediate the normalization of body weight that follows involuntary overfeeding, because it is only with this knowledge that we can clearly determine whether obesity is dependent on, or independent of, a failure in the weight regulatory system.

Introduction

Considerable progress has been made toward defining the physiological and cellular mechanisms regulating energy balance, particularly in response to weight loss. Acute and chronic periods of energy restriction induce significant changes in energy metabolism and behavior, and a reduction in circulating leptin appears to be a primary mediator of these changes. Preventing the fall of leptin is sufficient to attenuate many of the physiological events associated with negative energy balance, including alterations in energy expenditure, reproductive function, thyroid function, immune function, and neuroendocrine hormone secretion [1]. Low leptin levels also alter behavior and neural function, impinging on reward and memory, drug seeking behavior, electrical self-stimulation, conditioned-place preference, and the perception and response to food and food cues [2], [3], [4]. Thus settings of low leptin induce metabolic changes which preserve existing energy stores while simultaneously altering the brain such that the procurement and consumption of food becomes incredibly important. Leptin is certainly not the only component of this system, and the basic model continues to expand to include additional hormones, neuropeptides, and brain regions contributing to the regulation of energy balance [5], [6], [7], [8], [9].

Despite our increasing understanding of this system, obesity remains a significant health concern [10]. When exposed to highly palatable, energy dense diets, many humans and animals readily gain weight and adiposity. However, there is significant variability in this response, with some individuals effectively resisting weight gain despite being exposed to an obesigenic environment [11], [12]. Rodents also show a substantial individual variability in the susceptibility to diet-induced obesity [13], [14], [15], [16], [17], [18]. While a variety of mechanisms could contribute to this variability, several lines of evidence suggest that genetic or developmentally programmed differences in the weight regulatory system could contribute to differences in individual predisposition to obesity [19], [20], [21], [22], [23], [24].

The wide variation in weight gain on a high-fat diet highlights the difficulties inherent in using this model to define the response to positive energy balance. Therefore, some have used models of involuntary overfeeding to study positive energy balance, and this work provides evidence of a robust adaptive response. When animals are overfed either via gavage or intragastric infusion, a marked reduction of voluntary food intake occurs in addition to changes in metabolism [25], [26], [27]. More importantly, this reduction in food intake persists well beyond the cessation of overfeeding, lasting days or weeks depending on the degree of overfeeding and the rapidity of weight loss. Thus the voluntary hypophagia is not simply due to the presence of excess nutrients in the gut, but is instead an adaptive mechanism resulting in voluntary weight loss after overfeeding. In addition, work combining overfeeding with parabiosis demonstrates that overfeeding one animal reduces adiposity and alters metabolism in the parabiotic partner [28], [29]. These experimental paradigms provide strong evidence for an adaptive resistance to weight gain, at least when that gain is not being driven by voluntary consumption of highly palatable diets.

There is a distinct lack of information on the hormonal and molecular mechanisms mediating the adaptive response to involuntary overfeeding. A variety of hormones might contribute to this response, and evidence does indicate that overfeeding alters ghrelin, insulin and leptin levels [27], [30], [31], [32]. However, the degree to which these hormones contribute to the persistent hypophagia and weight loss following the cessation of overfeeding is unclear. Available evidence does implicate hypothalamic melanocortin signaling in this process, as overfeeding increased POMC expression within the mediobasal hypothalamus and intracerebroventricular administration of the melanocortin receptor antagonist SHU9119 following overfeeding attenuated the spontaneous hypophagia [33]. This outcome supports the hypothesis that POMC neurons are activated by overfeeding and contribute to adaptive decreases in food intake in response to positive energy balance. The mechanisms by which POMC neurons detect positive energy balance remain unclear. In an earlier study by the same group, it was noted that CRH expression was also significantly increased by overfeeding, but levels of NPY were not significantly decreased [27]. Again, these observations were made at the peak of overfeeding and it is unclear if these changes persist beyond the overfeeding treatment. In summary, these data indicate that mechanisms are in place to resist weight gain, as overfed animals do not remain at elevated body weights but instead spontaneously return to normal levels. While this adaptive response is most readily demonstrated when overfeeding is involuntarily imposed, it can also be observed in select individuals in a free feeding environment. Unfortunately, we know relatively little about the biological underpinnings of this resistance to weight gain, making it difficult to determine why this system appears inadequate or non-existent in certain individuals.