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Childhood obesity is associated with type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD). Recent studies have found associations between vitamin D deficiency (VDD), insulin resistance (IR), and NAFLD among overweight children. To further explore mechanisms mediating these effects, we fed young (age 25 days) Sprague-Dawley rats with a low-fat diet (LFD) alone or with vitamin D depletion (LFD1VDD). A second group of rats was exposed to a Westernized diet (WD: high-fat/high-fructose corn syrup) that is more typically consumed by overweight children, and was either replete (WD) or deficient in vitamin D (WD1VDD). Liver histology was assessed using the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) scoring system and expression of genes involved in inflammatory pathways were measured in liver and visceral adipose tissue after 10 weeks. In VDD groups, 25-OH-vitamin D levels were reduced to 29% (95% confidence interval [CI]: 23%-36%) compared to controls. WD1VDD animals exhibited significantly greater hepatic steatosis compared to LFD groups. Lobular inflammation as well as NAFLD Activity Score (NAS) were higher in WD1VDD versus the WD group (NAS: WD1VDD 3.2 6 0.47 versus WD 1.50 6 0.48, P < 0.05). Hepatic messenger RNA (mRNA) levels of Toll-like receptors (TLR)2, TLR4, and TLR9, as well as resistin, interleukins (IL)-1b, IL-4, and IL-6 and oxidative stress marker heme oxygenase (HO)-1, were higher in WD1VDD versus WD animals (P < 0.05). Logistic regression analyses showed significant associations between NAS score and liver mRNA levels of TLRs 2, 4, and 9, endotoxin receptor CD14, as well as peroxisome proliferator activated receptor (PPAR)c, and HO-1. Conclusion: VDD exacerbates NAFLD through TLR-activation, possibly by way of endotoxin exposure in a WD rat model. In addition it causes IR, higher hepatic resistin gene expression, and up-regulation of hepatic inflammatory and oxidative stress genes. (HEPATOLOGY 2012;55:1103-1111

The hormones insulin and leptin have been demonstrated to act in the central nervous system (CNS) as regulators of energy homeostasis at medial hypothalamic sites. In a previous review, we described new research demonstrating that, in addition to these direct homeostatic actions at the hypothalamus, CNS circuitry that subserves reward and motivation is also a direct and an indirect target for insulin and leptin action. Specifically, insulin and leptin can decrease food reward behaviors and modulate the function of neurotransmitter systems and neural circuitry that mediate food reward, i.e., midbrain dopamine and opioidergic pathways. Here we summarize new behavioral, systems, and cellular evidence in support of this hypothesis and in the context of research into the homeostatic roles of both hormones in the CNS. We discuss some current issues in the field that should provide additional insight into this hypothetical model. The understanding of neuroendocrine modulation of food reward, as well as food reward modulation by diet and obesity, may point to new directions for therapeutic approaches to overeating or eating disorders. motivation; food intake; dopamine

One of the defining characteristics of the research of Ann E. Kelley was her recognition that the neuroscience underlying basic learning and motivation processes also shed significant light upon mechanisms underlying drug addiction and maladaptive eating patterns. In this review, we examine the parallels that exist in the neural pathways that process both food and drug reward, as determined by recent studies in animal models and human neuroimaging experiments. We discuss contemporary research that suggests that hyperphagia leading to obesity is associated with substantial neurochemical changes in the brain. These findings verify the relevance of reward pathways for promoting consumption of palatable, calorically dense foods, and lead to the important question of whether changes in reward circuitry in response to intake of such foods serve a causal role in the development and maintenance of some cases of obesity. Finally, we discuss the potential value for future studies at the intersection of the obesity epidemic and the neuroscience of motivation, as well as the potential concerns that arise from viewing excessive food intake as an “addiction”. We suggest that it might be more useful to focus on overeating that results in frank obesity, and multiple health, interpersonal, and occupational negative consequences as a form of food “abuse”.

Figlewicz, Dianne P. Adiposity signals and food reward: expanding the CNS roles of insulin and leptin. Am J Physiol Regul Integr Comp Physiol 284: R882-R892, 2003;10.1152/ajpregu.00602.2002The hormones insulin and leptin have been proposed to act in the central nervous system (CNS) as adiposity signals as part of a theoretical negative feedback loop that senses the caloric stores of an animal and orchestrates adjustments in energy balance and food intake. Much research has provided support for both the existence of such a feedback loop and the specific roles that insulin and leptin may play. Most studies have focused on hypothalamic sites, which historically are implicated in the regulation of energy balance, and on the brain stem, which is a target for neural and humoral signals relating to ingestive acts. More recent lines of research, including studies from our lab, suggest that in addition to these CNS sites, brain reward circuitry may be a target for insulin and leptin action. These studies are reviewed together here with the goals of providing a historical overview of the findings that have substantiated the originally hypothesized negative feedback model and of opening up new lines of investigation that will build on these findings and allow further refinement of the model of adiposity signal/CNS feedback loop. The understanding of how motivational circuitry and its endocrine or neuroendocrine modulation contributes to normal energy balance regulation should expand possibilities for future therapeutic approaches to obesity and may lead to important insights into mental illnesses such as substance abuse or eating disorders. central nervous system; dopamine; food intake FROM HISTORICAL PERSPECTIVE TO MODERN PERSPECTIVEIn 1979, Porte, Woods, and colleagues (130) made the observation that putting a small amount of the metabolic hormone insulin directly into the cerebrospinal fluid (CSF) of nonhuman primates resulted in a significant decline in the animals' food intake and body weight. This observation was made in the context of ongoing studies in the field that suggested that a circulating humoral factor or factors could regulate both size of individual meals, as well as food intake and body weight, over a longer time course (31,83,90,117). In a subsequent review, Porte and Woods (94) proposed that insulin served as an "adiposity signal" whose levels in the brain reflected the size of adipose stores integrated over time and which served to complete a negative feedback loop that links the behavior of feeding with size of adipose stores, such that adipose mass remains fairly constant in adults over a relatively long time. Many studies over the intervening decades have essentially validated this basic concept (e.g., 3, 4, 15, 25, 84). In the mid-90s, a second candidate adiposity signal, Ob-protein or leptin, was identified (133), and the function of these two signals appears to be similar. A major research focus has been on the actions of these two hormones at the medial hypothalamus, which historically has be...

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We hypothesized that plasma insulin crosses the blood-cerebrospinal fluid (CSF) barrier and, as people gain weight, provides a physiological feedback signal to the central nervous system to inhibit food intake and further weight gain. However, it has not been demonstrated in man that insulin can enter the CSF from peripheral blood. To test whether increases in plasma insulin result in elevated CSF immunoreactive insulin (IRI) levels, we infused insulin iv in varying amounts approximating postprandial levels in eight normal subjects for 4.5 h. Euglycemia was maintained [88 +/- 3 (+/- SEM) mg/dl] by means of a variable glucose infusion. Samples were obtained every 30 min for measurements of insulin in peripheral plasma and insulin in lumbar CSF. Plasma IRI increased from a mean basal level of 12 +/- 1.2 microU/ml to a mean (during the 180- to 270-minute period) of 268 +/- 35 microU/ml. CSF IRI increased in all subjects during the infusion from a mean basal level of 0.9 +/- 0.1 microU/ml to a mean (during the 180- to 270-min period) of 2.8 +/- 0.4 microU/ml (P less than 0.006). By contrast, CSF IRI in two subjects who received an infusion of 0.9% saline did not increase. In summary, CSF insulin concentrations increased during peripheral infusions of insulin. This is the first demonstration in man that plasma insulin gains access to CSF and indicates a mechanism whereby peripheral insulin could provide a feedback signal to the central nervous system.