Location, location, location: the CNS sites of leptin action dictate its regulation of homeostatic and hedonic pathways

Abstract

The increasing incidence of obesity and obesity-linked disease presents a serious global health threat. To develop truly effective therapies to modulate food intake and promote weight loss, we must understand the physiological regulators that underlie these processes. One crucial mediator of food intake and energy homeostasis is the adipose-derived hormone, leptin, which acts through neurons expressing the long form of the leptin receptor (LepRb). Although most investigation of leptin action has centered on the large population of LepRb neurons in the arcuate nucleus (ARC), this nucleus does not mediate all aspects of leptin action. Indeed, several hypothalamic and extrahypothalamic loci contain substantial numbers of LepRb neurons, each of which presumably mediates distinct aspects of leptin action, and the collective output of these various LepRb populations produces the totality of leptin function. This review will examine known central nervous system loci that contain LepRb neurons and the potential roles for discrete populations of LepRb neurons in the control of homeostatic and hedonic pathways by leptin. Understanding the unique neuroanatomical and functional roles for each locus of leptin action will be important to identify how specific aspects of food intake contribute to obesity. International Journal of Obesity (2009) 33, S14-S17; doi:10.1038/ijo.2009.66Keywords: leptin; hypothalamus; energy balance; dopamine Leptin signaling is crucial for normal energy homeostasisThe incidence of obesity is increasing rapidly, predisposing millions of individuals to obesity-linked diseases such as type 2 diabetes that result in reduced life expectancy. In addition to the considerable personal toll exacted by obesity and its complications, the ongoing treatment of these conditions throughout a patient's life poses a staggering health care cost. These costs will only become more apparent with the dramatic ongoing rise in juvenile obesity that precipitates earlier onset of complications. Clearly, therapies to prevent weight gain and facilitate weight loss are needed, but our limited understanding of the systems that govern energy homeostasis has hindered the development of truly effective treatments.The discovery of leptin represents an important step in our understanding of how the body regulates food intake and energy homeostasis. Lack of leptin in rodents and humans results in obesity, diminished metabolic rate, hyperphagia and attenuated reproductive function. 1 Loss of the long form of the leptin receptor (LepRb) produces the same phenotype, showing the importance of leptin/ LepRb for normal physiology. 2 Although leptin is produced by adipocytes in approximate proportion to fat stores (that is, the more the adipose content, the more the leptin produced) and released into the circulation, LepRb is expressed, and leptin acts, primarily in the central nervous system on subsets of (primarily hypothalamic) neurons that control processes linked to the intake and expenditure of energy. 3 In aggregate, these clusters of...

Disruption of the Selenocysteine Lyase-Mediated Selenium Recycling Pathway Leads to Metabolic Syndrome in Mice

“…Increased circulating leptin leads to leptin resistance in specific areas of the brain where the presence of the leptin receptor controls feeding behavior and satiety. These areas are also known to be important for metabolic regulation, such as the choroid plexus (40) and ventromedial hypothalamus (34). To further corroborate the localized, hepatic effects of Scly disruption, immunostaining of the leptin receptor in these areas of the brain was performed.…”

Responses to drugs of abuse and non-drug rewards in leptin deficient ob/ob mice

“…Significant evidence suggests that novelty seeking is associated with mesolimbic dopamine transmission (Gjedde et al 2010; Olsen and Winder 2009; Rebec et al 1997). Leptin receptors are found within dopaminergic and non-dopaminergic neurons of the VTA, and leptin can regulate activity of VTA dopamine neurons both directly and indirectly (Hommel et al 2006; Leinninger 2009; Thompson and Borgland 2013). Ob/ob mice appear to have reduced mesolimbic dopamine signaling, as tyrosine hydroxylase (the rate limiting enzyme in catecholamine synthesis) and evoked dopamine release are reduced in these mice (Fulton et al 2006).…”

“…This phenotype is largely due to a lack of leptin signaling in neurons of the arcuate nucleus of the hypothalamus (Davis et al 2011; Friedman 1998; Houseknecht et al 1998). While the leptin receptors found in this area are classically associated with homeostatic feeding mechanisms, leptin receptors are also present in brain regions known to regulate hedonic-based feeding, natural reward processing, and responses to drugs of abuse (Leinninger 2009; Narayanan et al 2010). Specifically, the leptin receptor (LepRb) is found in the ventral tegmental area (VTA), nucleus tractis solitari, and lateral hypothalamus (Caron et al 2010; Figlewicz et al 2003; Scott et al 2009).…”

Oncogenic role and therapeutic target of leptin signaling in breast cancer and cancer stem cells

“…The biological role of leptin in energy homeostasis was demonstrated by normalization of hyperphagy and obese phenotypes with recombinant leptin administration in rodents and humans [29–30]. In addition, leptin plays critical roles in the regulation of glucose homeostasis, reproduction, growth and the immune response [31–33]. It is currently believed that leptin binding to Ob-R induces the extracellular domains of Ob-R to form a homodimer which constitutes the functional unit responsible for leptin-mediated signals.…”