Innate Fear-Induced Weight Regulation in the C57BL/6J Mouse.

Regulation of body weight is an important strategy for small prey animals to avoid capture. Field and laboratory studies have shown that prey animals reduce body size when subjected to long-term predator stimuli. However, the causes of predator-induced weight regulation are highly variable and the underlying mechanisms remain unclear. Understanding this phenomenon is important for gaining a better understanding of how animals regulate body weight under ethologically relevant conditions and has implications for obesity. Here we expose inbred C57BL/6J mice to a fear-inducing odorant (2,4,5-trimethylthiazole; mT) to model predation-induced weight regulation. Eight week-old mice were put on a 45% high fat diet (HFD) or chow diet (5% fat) and exposed daily to mT, an equally aversive dose of butyric acid (BA), or a neutral control scent (almond). mT-exposed mice in both diet groups gained significantly less weight over a 6-week period than BA-exposed mice. This differential weight gain appears unlikely to be due to differences in food intake and activity level, or brown adipose thermogenesis between the mT and BA groups. However, following chronic mT exposure we find increases in ΔFosB protein, a marker for long-term neural plasticity, in the dorsomedial hypothalamus (DMH)-an area previously implicated in chronic stress and defensive responses, as well as weight regulation. This study establishes a simplified and robust laboratory model of predation-mediated weight regulation with inbred lab mice and fear-inducing odor, and suggests a likely, yet undetermined, metabolic adaptation as contributing to this response.

Vitamin D3: A Role in Dopamine Circuit Regulation, Diet-Induced Obesity, and Drug Consumption.

The influence of micronutrients on dopamine systems is not well defined. Using mice, we show a potential role for reduced dietary vitamin D3 (cholecalciferol) in promoting diet-induced obesity (DIO), food intake, and drug consumption while on a high fat diet. To complement these deficiency studies, treatments with exogenous fully active vitamin D3 (calcitriol, 10 µg/kg, i.p.) were performed. Nondeficient mice that were made leptin resistant with a high fat diet displayed reduced food intake and body weight after an acute treatment with exogenous calcitriol. Dopamine neurons in the midbrain and their target neurons in the striatum were found to express vitamin D3 receptor protein. Acute calcitriol treatment led to transcriptional changes of dopamine-related genes in these regions in naive mice, enhanced amphetamine-induced dopamine release in both naive mice and rats, and increased locomotor activity after acute amphetamine treatment (2.5 mg/kg, i.p.). Alternatively, mice that were chronically fed either the reduced D3 high fat or chow diets displayed less activity after acute amphetamine treatment compared with their respective controls. Finally, high fat deficient mice that were trained to orally consume liquid amphetamine (90 mg/L) displayed increased consumption, while nondeficient mice treated with calcitriol showed reduced consumption. Our findings suggest that reduced dietary D3 may be a contributing environmental factor enhancing DIO as well as drug intake while eating a high fat diet. Moreover, these data demonstrate that dopamine circuits are modulated by D3 signaling, and may serve as direct or indirect targets for exogenous calcitriol.

Gene profiling reveals a role for stress hormones in the molecular and behavioral response to food restriction.

BACKGROUND: Food restriction is known to enhance learning and motivation. The neural mechanisms underlying these responses likely involve alterations in gene expression in brain regions mediating the motivation to feed. METHODS: Analysis of gene expression profiles in male C57BL/6J mice using whole-genome microarrays was completed in the medial prefrontal cortex, nucleus accumbens, ventral tegmental area, and the hypothalamus following a 5-day food restriction. Quantitative polymerase chain reaction was used to validate these findings and determine the time course of expression changes. Plasma levels of the stress hormone corticosterone (CORT) were measured by enzyme-linked immunosorbent assay. Expression changes were measured in adrenalectomized animals that underwent food restriction, as well as in animals receiving daily injections of CORT. Progressive ratio responding for food, a measure of motivated behavior, was assessed after CORT treatment in restricted and fed animals. RESULTS: Brief food restriction results in an upregulation of peripheral stress responsive genes in the mammalian brain. Time-course analysis demonstrated rapid and persistent expression changes in all four brain regions under study. Administration of CORT to nonrestricted animals was sufficient to induce a subset of the genes, and alterations in gene expression after food restriction were dependent on intact adrenal glands. CORT can increase the motivation to work for food only in the restricted state. CONCLUSIONS: These data demonstrate a central role for CORT in mediating both molecular and behavioral responses to food restriction. The stress hormone-induced alterations in gene expression described here may be relevant for both adaptive and pathological responses to stress.