The prevalence of obesity and related disorders such as diabetes has skyrocketed worldwide despite efforts to therapeutically target homeostatic mechanisms that regulate appetite, energy expenditure, and weight gain. The failure of these efforts points to the existence of additional, nonhomeostatic mechanisms that mediate feeding behavior (Palmiter, 2007). Indeed, redundancy in these systems makes obesity therapy difficult as further evidenced by the failure of newer drugs targeting distinct aspects of these systems. Thus, the epidemic of obesity begs for novel concepts and therapeutic targets that ideally treat ‘food-use' disorders and related comorbidities such as drug addiction and neuropsychiatric disorders.
Nonhomeostatic or ‘reward' circuits originating in dopamine-rich brain structures, which provide motivation and reward stimuli for feeding, are increasingly understood at the cellular and molecular levels (Palmiter, 2007). Long recognized as an important mediator of feeding behavior, dopamine signaling is increasingly of interest in obesity with findings that dopamine D2 receptor binding is reduced in a BMI-dependent manner (Wang et al, 2001). Building on this observation, current models of obesity pathogenesis posit that dopaminergic dysfunction, referred to as hypodopaminergic reward deficiency syndrome (HRDS), has a predisposing and/or causative role (Wang et al, 2001). HRDS shares features of impaired striatal dopamine neurotransmission with substance use disorders (Wang et al, 2001).
Insulin is a glucoregulatory hormone in the periphery that functions in the CNS to regulate both homeostatic and reward-based high-fat feeding (Figlewicz and Benoit, 2009). Insulin receptors are abundant in CNS, including striatum and hypothalamus where insulin action serves functions ranging from signaling peripheral metabolic status, to regulation of reward, development, cognition, and others. We, and others, have hypothesized that identification of a molecular link between brain insulin signaling and dopaminergic-related behaviors would have the potential to explain susceptibility to ‘food-use' disorders. Therefore, strategies aimed at improving brain dopamine function in obesity may be a possible solution.
We and others have distilled the molecular mechanism by which CNS monoaminergic systems are regulated by insulin (Robertson et al, 2010; Williams et al, 2007). That neuronal insulin signaling is exquisitely sensitive to dietary macronutrient intake (Posey et al, 2009) (fat and sugar) allows us to propose a transformative potential molecular mechanism for the pathogenesis of obesity. These observations, and similar findings from others, suggest a link between brain insulin signaling and monoamine-related behaviors. Disruption of brain insulin action (genetic or acquired) may, therefore, confer risk for and/or underlie ‘food-use'—as well as a range of neurocognitive and psychiatric—disorders. This molecular model, thus, explains how even short-term exposure to ‘the fast food lifestyle' creates a vicious cycle of disordered eating that cements pathological changes in dopamine signaling leading to weight gain, and obesity.
We propose that intact insulin signaling in dopamine-rich brain regions supports dopamine homeostasis and normal reward for food. In our modern, energy-dense food environment, reward drives poor dietary decisions where reward-driven overconsumption of high-fat, high-sugar, energy-dense foods quickly leads to neuronal insulin resistance, dysregulation of dopamine homeostasis, and HRDS. In this stage of pathogenesis, HRDS, described in obese humans, is established (Wang et al, 2001). This ‘syndrome' results in chronically increased intake of fat and sugar to achieve a normal level of reward in the setting of decreased dopamine tone.