Hypothalamic AMPK as a Regulator of Energy Homeostasis

Activated in energy depletion conditions, AMP-activated protein kinase (AMPK) acts as a cellular energy sensor and regulator in both central nervous system and peripheral organs. Hypothalamic AMPK restores energy balance by promoting feeding behavior to increase energy intake, increasing glucose production, and reducing thermogenesis to decrease energy output. Besides energy state, many hormones have been shown to act in concert with AMPK to mediate their anorexigenic and orexigenic central effects as well as thermogenic influences. Here we explore the factors that affect hypothalamic AMPK activity and give the underlying mechanisms for the role of central AMPK in energy homeostasis together with the physiological effects of hypothalamic AMPK on energy balance restoration

Hypothalamic AMPK as a Regulator of Energy Homeostasis

Activated in energy depletion conditions, AMP-activated protein kinase (AMPK) acts as a cellular energy sensor and regulator in both central nervous system and peripheral organs. Hypothalamic AMPK restores energy balance by promoting feeding behavior to increase energy intake, increasing glucose production, and reducing thermogenesis to decrease energy output. Besides energy state, many hormones have been shown to act in concert with AMPK to mediate their anorexigenic and orexigenic central effects as well as thermogenic influences. Here we explore the factors that affect hypothalamic AMPK activity and give the underlying mechanisms for the role of central AMPK in energy homeostasis together with the physiological effects of hypothalamic AMPK on energy balance restoration

Breadth of antibodies to Plasmodium falciparum variant surface antigens is associated with immunity in a controlled human malaria infection study

Background: Plasmodium falciparum variant surface antigens (VSAs) contribute to malaria pathogenesis by mediating cytoadhesion of infected red blood cells to the microvasculature endothelium. In this study, we investigated the association between anti-VSA antibodies and clinical outcome in a controlled human malaria infection (CHMI) study. Method: We used flow cytometry and ELISA to measure levels of IgG antibodies to VSAs of five heterologous and one homologous P. falciparum parasite isolates, and to two PfEMP1 DBLβ domains in blood samples collected a day before the challenge and 14 days after infection. We also measured the ability of an individual’s plasma to inhibit the interaction between PfEMP1 and ICAM1 using competition ELISA. We then assessed the association between the antibody levels, function, and CHMI defined clinical outcome during a 21-day follow-up period post infection using Cox proportional hazards regression. Results: Antibody levels to the individual isolate VSAs, or to two ICAM1-binding DBLβ domains of PfEMP1, were not associated with a significantly reduced risk of developing parasitemia or of meeting treatment criteria after the challenge after adjusting for exposure. However, anti-VSA antibody breadth (i.e., cumulative response to all the isolates) was a significant predictor of reduced risk of requiring treatment [HR 0.23 (0.10-0.50) p= 0.0002]. Conclusion: The breadth of IgG antibodies to VSAs, but not to individual isolate VSAs, is associated with protection in CHMI

Steroidogenic Factor 1 in the Ventromedial Nucleus of the Hypothalamus Regulates Age-Dependent Obesity

<div><p>The ventromedial nucleus of the hypothalamus (VMH) is important for the regulation of whole body energy homeostasis and lesions in the VMH are reported to result in massive weight gain. The nuclear receptor steroidogenic factor 1 (SF-1) is a known VMH marker as it is exclusively expressed in the VMH region of the brain. SF-1 plays a critical role not only in the development of VMH but also in its physiological functions. In this study, we generated prenatal VMH-specific SF-1 KO mice and investigated age-dependent energy homeostasis regulation by SF-1. Deletion of SF-1 in the VMH resulted in dysregulated insulin and leptin homeostasis and late onset obesity due to increased food intake under normal chow and high fat diet conditions. In addition, SF-1 ablation was accompanied by a marked reduction in energy expenditure and physical activity and this effect was significantly pronounced in the aged mice. Taken together, our data indicates that SF-1 is a key component in the VMH-mediated regulation of energy homeostasis and implies that SF-1 plays a protective role against metabolic stressors including aging and high fat diet.</p></div

SF-1 deletion leads to impaired gene expression in BAT and blunted Vglut2 expression in the VMH.

<p>(A) UCP1, (B) β3AR, and (C) PPARγ expression in brown adipose tissue (BAT) in young male mice (12 weeks). (D) In situ hybridization analyses of Vglut2 expression in the VMH. The number of animals examined is expressed in the parenthesis. Scale bar = 200μm, The data are represented as mean ± SEM (*<i>P</i> < 0.05, Student’s t-test).</p

Metabolic phenotypes of young and old VMH-specific SF-1 KO mice.

<p>(A and E) percentage body weight, (B and F) daily food intake, (C and G) blood insulin levels, (D and H) blood leptin levels. (A-D) 20–30 weeks old male mice. (E-H) 45–55 weeks old male mice. The number of animals examined is expressed in the parenthesis. The data are represented as mean ± SEM (*<i>P</i> < 0.05, Student’s t-test).</p

Regulation of energy expenditure by SF-1 in metabolic stress condition.

<p>(A) O₂ consumption, (B) heat generation, (C) ambulatory movement, (D) rearing movement, (E) body weight, (F) blood insulin levels, (G) blood leptin levels, (H) glucose levels. (A-D) 45–55 weeks old male mice. (E-H) 20–30 weeks old male mice challenged with high fat diet for three weeks. Figures in parenthesis indicate number of animals studied. The data are represented as mean ± SEM (*<i>P</i> < 0.05, Student’s <i>t</i>-test for bar graphs and two-way ANOVA for comparison of multiple time points). BB, beam break.</p

Impaired energy expenditure in SF-1 KO mice under high fat diet.

<p>(A and B) O₂ consumption, (C and D) CO₂ production, (E and F) heat generation. (A-F) 20–30 weeks old male mice. Figures in parenthesis indicate number of animals studied. The data are represented as mean ± SEM (*<i>P</i> < 0.05, Student’s t-test). HFD, high fat diet.</p