Disruption of lipid uptake in astroglia exacerbates diet induced obesity.

Neuronal circuits in the brain help to control feeding behavior and systemic metabolism in response to afferent nutrient and hormonal signals. Although astrocytes have historically been assumed to be less relevant for such neuroendocrine control, we asked whether lipid uptake via lipoprotein lipase (LPL) in astrocytes is required for the central regulation of energy homeostasis. Ex vivo studies with hypothalamic-derived astrocytes showed that LPL expression is up-regulated by oleic acid; whereas it is decreased in response to palmitic acid or triglyceride. Likewise, astrocytic LPL deletion reduced the accumulation of lipid drops in those glial cells. Consecutive in vivo studies showed that the postnatal ablation of LPL in glial fibrillary acidic protein (GFAP)-expressing astrocytes induced exaggerated body weight gain and glucose intolerance in mice exposed to a high-fat diet (HFD). Intriguingly, astrocytic LPL deficiency also triggered increased ceramide content in the hypothalamus, which may contribute to hypothalamic insulin resistance. We conclude that hypothalamic LPL functions in astrocytes to ensure appropriately balanced nutrient sensing, ceramide distribution, body weight regulation and glucose metabolism

TNF alpha drives mitochondrial stress in POMC neurons in obesity

Consuming a calorically dense diet stimulates microglial reactivity in the mediobasal hypothalamus (MBH) in association with decreased number of appetite-curbing pro-opiomelanocortin (POMC) neurons; whether the reduction in POMC neuronal function is secondary to the microglial activation is unclear. Here we show that in hypercaloric diet-induced obese mice, persistently activated microglia in the MBH hypersecrete TNF alpha that in turn stimulate mitochondrial ATP production in POMC neurons, promoting mitochondrial fusion in their neurites, and increasing POMC neuronal firing rates and excitability. Specific disruption of the gene expressions of TNF alpha downstream signals TNFSF11A or NDUFAB1 in the MBH of diet-induced obese mice reverses mitochondrial elongation and reduces obesity. These data imply that in a hypercaloric environment, persistent elevation of microglial reactivity and consequent TNF alpha secretion induces mitochondrial stress in POMC neurons that contributes to the development of obesit

Dietary sugars, not lipids, drive hypothalamic inflammation

OBJECTIVE: The hypothalamus of hypercaloric diet-induced obese animals is featured by a significant increase of microglial reactivity and its associated cytokine production. However, the role of dietary components, in particular fat and carbohydrate, with respect to the hypothalamic inflammatory response and the consequent impact on hypothalamic control of energy homeostasis is yet not clear. METHODS: We dissected the different effects of high-carbohydrate high-fat (HCHF) diets and low-carbohydrate high-fat (LCHF) diets on hypothalamic inflammatory responses in neurons and non-neuronal cells and tested the hypothesis that HCHF diets induce hypothalamic inflammation via advanced glycation end-products (AGEs) using mice lacking advanced glycation end-products (AGEs) receptor (RAGE) and/or the activated leukocyte cell-adhesion molecule (ALCAM). RESULTS: We found that consumption of HCHF diets, but not of LCHF diets, increases microgliosis as well as the presence of N(ε)-(Carboxymethyl)-Lysine (CML), a major AGE, in POMC and NPY neurons of the arcuate nucleus. Neuron-secreted CML binds to both RAGE and ALCAM, which are expressed on endothelial cells, microglia, and pericytes. On a HCHF diet, mice lacking the RAGE and ALCAM genes displayed less microglial reactivity and less neovasculature formation in the hypothalamic ARC, and this was associated with significant improvements of metabolic disorders induced by the HCHF diet. CONCLUSIONS: Combined overconsumption of fat and sugar, but not the overconsumption of fat per se, leads to excessive CML production in hypothalamic neurons, which, in turn, stimulates hypothalamic inflammatory responses such as microgliosis and eventually leads to neuronal dysfunction in the control of energy metabolism

Performance of turbo high-pitch dual-source CT for coronary CT angiography: first ex vivo and patient experience

OBJECTIVES: To evaluate image quality, maximal heart rate allowing for diagnostic imaging, and radiation dose of turbo high-pitch dual-source coronary computed tomographic angiography (CCTA). METHODS: First, a cardiac motion phantom simulating heart rates (HRs) from 60-90 bpm in 5-bpm steps was examined on a third-generation dual-source 192-slice CT (prospective ECG-triggering, pitch 3.2; rotation time, 250 ms). Subjective image quality regarding the presence of motion artefacts was interpreted by two readers on a four-point scale (1, excellent; 4, non-diagnostic). Objective image quality was assessed by calculating distortion vectors. Thereafter, 20 consecutive patients (median, 50 years) undergoing clinically indicated CCTA were included. RESULTS: In the phantom study, image quality was rated diagnostic up to the HR75 bpm, with object distortion being 1 mm or less. Distortion increased above 1 mm at HR of 80-90 bpm. Patients had a mean HR of 66 bpm (47-78 bpm). Coronary segments were of diagnostic image quality for all patients with HR up to 73 bpm. Average effective radiation dose in patients was 0.6 ± 0.3 mSv. CONCLUSIONS: Our combined phantom and patient study indicates that CCTA with turbo high-pitch third-generation dual-source 192-slice CT can be performed at HR up to 75 bpm while maintaining diagnostic image quality, being associated with an average radiation dose of 0.6 mSv. KEY POINTS: • CCTA is feasible with the turbo high-pitch mode. • Turbo high-pitch CCTA provides diagnostic image quality up to 73 bpm. • The radiation dose of high-pitch CCTA is 0.6 mSv on average