Making an "Obese"Brain(and Body)Lean: Insulin Detemir,Monoamines,and Reward

Together with obesity, diabetes is epidemic in the US (20) and worldwide (21). Increased body weight is both a risk factor for diabetes (22) and a consequence of initiation and intensification of insulin therapy, as illustrated in landmark diabetes control trials (1-3). Weight gain can worsen insulin resistance leading to higher insulin requirements, and, thus perpetuates a vicious cycle (36), the ultimate effect of which may be to further enhance metabolic risk (15, 35). For example, an analysis of the diabetes control and complications trial (DCCT) revealed that the highest quartile of weight gain in the intensive treatment led to hyperlipidemia and increased blood pressure; i.e. metabolic syndrome (35). Thus, while glycemic control is clearly a critical metabolic target in diabetes outcomes, additional considerations, including body weight (adiposity) and weight gain, are of fundamental importance in the clinical management of a complex disease such as diabetes. Of course, overweight and obesity are clearly a critical risk factor for the development of type II diabetes in the first place (10), and further weight gain generates significant negative "biofeedback" to the patient and physician struggling to achieve control(33).

Mechanisms involved in weight gain on insulin therapy are incompletely understood: hypoglycemia is potent stimulus to feed (11), improving glycemic control reverses the negative energy balance associated with glycosuria (loss of energy as glucose through the urine), and insulin is clearly a potent anabolic hormone in peripheral tissues (37). In contrast to ample evidence associating insulin therapy with weight gain, a distinct body of evidence indicates that insulin functions as an adiposity negative feedback signal to the brain (23) and limits food intake and weight gain. It is now generally accepted that insulin plays an important role in the neural control of energy homeostasis (matching of caloric intake to energy expenditure to maintain body weight) as well as glucose homeostasis via such neural effects (23). Of course, as will be further discussed, insulin has numerous effects in the CNS ranging from modulation of reward (12), cognition (31), and mood (32). Indeed, the overarching hypothesis of this study is that insulin modulates brain function in a manner that is beneficial.

Food reward can loosely be described as the processes involved in liking, wanting, and learning to acquire food and each of these aspects represent separate but overlapping neuropsychological substrates. To put it even more simply, reward is the sense of satisfaction or pleasure derived from eating. Food reward has sensory, integrative, and motor components, all of which contribute to consummatory behaviors (38). Relevant to the focus of this particular study, is the monoamine neurotransmitter dopamine, which is heavily involved in the generation of food reward. Insulin, a signal generated in response to food intake, functions to decrease, or control food reward(12).

Reward, defined as the sense of satisfaction, or indeed, pleasure that results from feeding is an increasingly recognized and potentially potent influence over food intake that shares neuoranatomical and neurochemical correlates with substance abuse (although with clear differences as well). Although other neurotransmitters (in particular opioids and endocannabinoids) are involved in reward, the monoamine neurotransmitter, dopamine (DA) has been strongly implicated in mediating reward from food (and other stimuli). The midbrain is particularly rich in dopamine neurons, originating in the ventral tegmental area (VTA) that project to both ventral (nucleus accumbens, NAc) and dorsal (caudate and putamen) striatum, brain areas that integrate and subserve reward and food seeking behaviors. While the circuitry involved in feeding and reward is complex, these discreet brain areas (dorsal and ventral striatum) are heavily dopaminergic, implicated in reward, and are brain areas that our group has a great deal of expertise in studying.

Dopamine is secreted into the synapse from pre-synaptic nerve terminals and either binds to and activates dopamine receptor signaling, or is cleared from the synaptic cleft by a specific transporter molecule. The dopamine receptor of interest for this study is the D2 receptor, as it has been well studied and is the isoform involved in feeding. Similarly, the dopamine transporter has been well studied, plays a critical role in dopamine neurotransmission, and is regulated by insulin. In this study we will utilize PET radioligands to quantify expression of D2 receptors. We will additionally utilize functional brain imaging (functional magnetic resonance imaging (fMRI)) to quantify changes in dopamine circuits in response to food cues (visual images of obesogenic food) and in response to a probe of dopamine transporter function.