Identification of a brain fingerprint for overweight and obesity.

The brain plays a central role in the pathophysiology of overweight and obesity. Connectome-based Predictive Modeling (CPM) is a newly developed, data-driven approach that exploits whole-brain functional connectivity to predict a behavior or trait that varies across individuals. We used CPM to determine whether brain "fingerprints" evoked during milkshake consumption could be isolated for common measures of adiposity in 67 adults with overweight and obesity. We found that CPM captures more variance in waist circumference than either percent body fat or BMI, the most frequently used measures to assess brain correlates of obesity. In a post-hoc analysis, we were also able to derive a largely separable functional connectivity network predicting fasting blood insulin. These findings suggest that, in individuals with overweight and obesity, brain network patterns may be more tightly coupled to waist circumference than BMI or percent body fat and that adiposity and glucose tolerance are associated with distinct maps, pointing to dissociable central pathophysiological phenotypes for obesity and diabetes.

Effects of the modern food environment on striatal function, cognition and regulation of ingestive behavior.

Emerging evidence from human and animal studies suggest that consumption of palatable foods rich in fat and/or carbohydrates may produce deleterious influences on brain function independently of body weight or metabolic disease. Here we consider two mechanisms by which diet can impact striatal circuits to amplify food cue reactivity and impair inhibitory control. First, we review findings demonstrating that the energetic properties of foods regulate nucleus accumbens food cue reactivity, a demonstrated predictor of weight gain susceptibility, which is then sensitized by chronic consumption of an energy dense diet. Second, we consider evidence for diet-induced adaptations in dorsal striatal dopamine signaling that is associated with impaired inhibitory control and negative outcome learning.

Physiological mechanisms by which non-nutritive sweeteners may impact body weight and metabolism.

Evidence linking sugar-sweetened beverage (SSB) consumption to weight gain and other negative health outcomes has prompted many individuals to resort to artificial, non-nutritive sweetener (NNS) substitutes as a means of reducing SSB intake. However, there is a great deal of controversy regarding the biological consequences of NNS use, with accumulating evidence suggesting that NNS consumption may influence feeding and metabolism via a variety of peripheral and central mechanisms. Here we argue that NNSs are not physiologically inert compounds and consider the potential biological mechanisms by which NNS consumption may impact energy balance and metabolic function, including actions on oral and extra-oral sweet taste receptors, and effects on metabolic hormone secretion, cognitive processes (e.g. reward learning, memory, and taste perception), and gut microbiota.

Striatal serotonin 2C receptors decrease nigrostriatal dopamine release by increasing GABA-A receptor tone in the substantia nigra.

Drugs acting at the serotonin-2C (5-HT2C) receptor subtype have shown promise as therapeutics in multiple syndromes including obesity, depression, and Parkinson's disease. While it is established that 5-HT2C receptor stimulation inhibits DA release, the neural circuits and the localization of the relevant 5-HT2C receptors remain unknown. This study used dual-probe in vivo microdialysis to investigate the relative contributions of 5-HT2C receptors localized in the rat substantia nigra (SN) and caudate-putamen (CP) in the control of nigrostriatal DA release. Systemic administration (3.0 mg/kg) of the 5-HT2C receptor selective agonist Ro 60-0175 [(αS)-6-Chloro-5-fluoro-α-methyl-1H-indole-1-ethanamine fumarate] decreased, whereas intrastriatal infusions of the selective 5-HT2C antagonist SB 242084 [6-Chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide; 1.0 µM] increased, basal DA in the CP. Depending on the site within the SN pars reticulata (SNpr), infusions of SB 242084 had more modest but significant effects. Moreover, infusions of the GABA-A receptor agonist muscimol (10 µM) into the SNpr completely reversed the increases in striatal DA release produced by intrastriatal infusions of SB 242084. These findings suggest a role for 5-HT2C receptors regulating striatal DA release that is highly localized. 5-HT2C receptors localized in the striatum may represent a primary site of action that is mediated by the actions on GABAergic activity in the SN. Dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) project to the caudate-putamen (CP; striatum). This circuitry is implicated in numerous pathologies including Parkinson's disease. Using in vivo microdialysis, we demonstrated that blockade of serotonin (5-HT) 2C receptors in the CP increased nigrostriatal DA release. Infusions of a GABA-A agonist into the substantia nigra pars reticulata (SNpr) blocked this increase. This work indicates that striatal serotonin 2C receptors regulate GABAergic tone in the SNpr, which in turn regulates nigrostriatal DA release.