Deficiency of Complement Component C1Q Prevents Cerebrovascular Damage and White Matter Loss in a Mouse Model of Chronic Obesity.

Age-related cognitive decline and many dementias involve complex interactions of both genetic and environmental risk factors. Recent evidence has demonstrated a strong association of obesity with the development of dementia. Furthermore, white matter damage is found in obese subjects and mouse models of obesity. Here, we found that components of the complement cascade, including complement component 1qa (C1QA) and C3 are increased in the brain of Western diet (WD)-fed obese mice, particularly in white matter regions. To functionally test the role of the complement cascade in obesity-induced brain pathology, female and male mice deficient in C1QA, an essential molecule in the activation of the classical pathway of the complement cascade, were fed a WD and compared with WD-fed wild type (WT) mice, and t

Dysregulation of the Norepinephrine Transporter Sustains Cortical Hypodopaminergia and Schizophrenia-Like Behaviors in Neuronal Rictor Null Mice

A novel animal model highlights the link between Akt dysfunction, reduced cortical dopamine function, norepinephrine transporters, and schizophrenia-like behaviors

Neuronal PPARδ deletion alters hypothalamic neuropeptide gene expression and compensatory hyperphagia after prolonged fasting.

<p>Hypothalamic mRNA levels of neuropeptides in f/f and KO mice fed LFD or HFD for 33 weeks (n = 6–7). Target gene mRNA levels of (A) NPY and (B) POMC were assessed by quantitative RT PCR. (C–D) Fasting induced changes in hypothalamic neuropeptide mRNA levels of f/f and KO mice maintained on a chow diet or fasted for 24 hours. Target gene mRNA levels of (C) NPY, (D) POMC and (E) UCP2 in fed and fasted mice were normalized to RPL13A and are expressed relative to the f/f, fed control. (F) Refeeding after fasting was measured for an additional 24 hours in a separate cohort of individually housed chow fed mice (n = 6–7). Graph shows food intake normalized to basal, pre-fast lean mass (kcal/g lean mass). (G) Percent changes in body weight after a 24 hour fast, after fasting and refeeding for 24 hours, or an additional 7 days. Values represent the mean ± SEM. Statistical significance in panel A–E is designated as ^a (<i>p</i><0.05 f/f <i>vs.</i> KO, same diet) or <i>^b</i> (<i>p</i><0.05, LF <i>vs.</i> HF, same genotype), as determined by two-way ANOVA and Bonferroni post test, and in F and G by * (<i>p</i><0.05 <i>vs.</i> f/f), as determined by two-tailed student's <i>t</i> test.</p

Neuron-Specific Deletion of Peroxisome Proliferator-Activated Receptor Delta (PPARδ) in Mice Leads to Increased Susceptibility to Diet-Induced Obesity

<div><p>Central nervous system (CNS) lipid accumulation, inflammation and resistance to adipo-regulatory hormones, such as insulin and leptin, are implicated in the pathogenesis of diet-induced obesity (DIO). Peroxisome proliferator-activated receptors (PPAR α, δ, γ) are nuclear transcription factors that act as environmental fatty acid sensors and regulate genes involved in lipid metabolism and inflammation in response to dietary and endogenous fatty acid ligands. All three PPAR isoforms are expressed in the CNS at different levels. Recent evidence suggests that activation of CNS PPARα and/or PPARγ may contribute to weight gain and obesity. PPARδ is the most abundant isoform in the CNS and is enriched in the hypothalamus, a region of the brain involved in energy homeostasis regulation. Because in peripheral tissues, expression of PPARδ increases lipid oxidative genes and opposes inflammation, we hypothesized that CNS PPARδ protects against the development of DIO. Indeed, genetic neuronal deletion using Nes-Cre loxP technology led to elevated fat mass and decreased lean mass on low-fat diet (LFD), accompanied by leptin resistance and hypothalamic inflammation. Impaired regulation of neuropeptide expression, as well as uncoupling protein 2, and abnormal responses to a metabolic challenge, such as fasting, also occur in the absence of neuronal PPARδ. Consistent with our hypothesis, KO mice gain significantly more fat mass on a high-fat diet (HFD), yet are surprisingly resistant to diet-induced elevations in CNS inflammation and lipid accumulation. We detected evidence of upregulation of PPARγ and target genes of both PPARα and PPARγ, as well as genes of fatty acid oxidation. Thus, our data reveal a previously underappreciated role for neuronal PPARδ in the regulation of body composition, feeding responses, and in the regulation of hypothalamic gene expression.</p> </div

Effects of dietary fat and PPARδ deletion on brain lipids, fatty acid composition and lipid metabolism genes.

<p>(A) Total levels of triglyceride (TG), diglyceride (DG) and free fatty acid (FFA) extracted from total lipids from brains of f/f and KO mice fed LFD or HFD for 33 weeks (n = 6–7). Composition of individual FFA species making up the (C) FFA and (E) TG fractions were determined by GC-MS analysis, normalized to brain tissue mass (ng/mg tissue) and shown as group mean±SEM. (B) Changes in hypothalamic mRNA levels of target genes involved in (B) lipid uptake and storage (LPL, CD36, GPAT and DGAT), (D) lipid synthesis (FAS, ACC, SCD) and (F) fatty acid oxidation (ACO, PDK4, CPT1A, UCP2) were assessed by quantitative real-time PCR. Gene expression levels were normalized to endogenous RPL13A levels and are expressed as group mean±SEM relative to the level of the f/f LF diet control group. Statistical significance is designated as ^a (<i>p</i><0.05, f/f <i>vs.</i> KO, same diet) or <i>^b</i> (<i>p</i><0.05, LF <i>vs.</i> HF, same genotype), as determined by one-way ANOVA and Bonferroni post test.</p

Effects of neuronal PPARδ deletion on hypothalamic PPARγ and PPARα expression.

<p>Hypothalamic mRNA expression of PPAR isoforms in f/f and KO mice fed LFD or HFD for 33 weeks was assessed by quantitative real-time PCR. Changes in PPARδ, PPARγ and PPARα were normalized to endogenous RPL13A levels and expressed relative to that of the f/f LFD group. Values represent group mean±SEM (n = 6–7). Statistical significance is designated ^a (<i>p</i><0.05, f/f <i>vs.</i> KO, same diet) or <i>^b</i> (<i>p</i><0.05, LF <i>vs.</i> HF, same genotype), as determined by two-way ANOVA and Bonferroni post test.</p

Neuronal PPARδ deletion leads to leptin insensitivity.

<p>(<b>A</b>) Food intake in chow fed f/f and KO mice after receiving a bolus injection of leptin (5 mg/kg BW, i.p.) or vehicle (saline) at the onset of the dark period. Mice were housed individually and food intake was measured over 24 hours (n = 10–12). (B) Hypothalamic total protein extracts from f/f and KO mice treated with leptin (5 mg/kg BW i.p.) or vehicle for 30 minutes were used for Western blot analysis to detect levels of STAT3 phosphorylation (Y705). Total STAT3 levels were determined and used as a loading control. Densitometery of blots yielded relative intensity of protein levels, which are expressed as an activation index (pSTAT3/total STAT3) and represented as the group mean ±SEM (n = 4–6) relative to the f/f saline group. (C) Epigonadal fat pad mass and (D) plasma leptin levels of aged matched, chow fed f/f and KO mice represent basal phenotype of these mice. Values represent the mean ± SEM. Statistical significance is denoted in A and B as * (<i>p</i><0.05 leptin (gray bars) <i>vs.</i> vehicle (white bars) treated groups within each mouse genotype) or # (<i>p</i><0.05, KO <i>vs.</i> f/f mice treated with leptin), and in panels C and D as * (<i>p</i><0.05 <i>vs.</i> f/.f controls, two-tailed student's <i>t</i> test).</p

Energy homeostasis analysis after 20 weeks of high-fat diet (HFD) exposure.

<p>Energy expenditure (EE) and respiratory exchange ratio (RER) were measured over 24 hours by indirect calorimetry in individually housed f/f and KO mice after 20 weeks on HFD (n = 4). Values for EE (kcal/hour) and food intake were also normalized to body weight and lean body mass measured by NMR. Mean ± SEM,</p>*<p>p<0.05,</p>**<p>p<0.01,</p>***<p>p<0.001 KO vs. f/f same diet, Student's <i>t</i> test.</p

Neuronal PPARδ knockdown and brain morphology.

<p>(A) PPARδ gene expression in mediobasal hypothalamus of control (f/f), heterozygous KO (het) and homozygous KO (KO) PPARδ mice. Target gene PPARδ mRNA expression was measured by RT PCR and normalized to endogenous levels of the housekeeping gene RPL13A. (B) Representative Western blot of PPARδ protein levels in total cellular protein extracts from mediobasal hypothalamus of f/f and KO mice. β-tubulin was used as a loading control. (C) Quantification of PPARδ mRNA expression in peripheral and CNS tissues of f/f and KO mice (muscle, liver, white adipose tissue (WAT), brown adipose tissue (BAT), cerebral cortex and hypothalamus). Gene expression was measured by RT PCR and normalized to endogenous levels of the housekeeping gene RPL13A (n = 4–8). (D) Photomicrographs of Nissl staining in brains from f/f, nestin cre+ control and KO mice. Representative sections shown at the level of the hippocampus (top) and hypothalamus (bottom). No obvious differences or malformations in the structure of these or any other forebrain nuclei were observed across genotypes. Scale bar = 500 µm. Values in panels A and C represent the genotype group mean ± SEM, expressed relative to the levels of the f/f control group. Statistical significance is designated as * (<i>p</i><0.05, <i>vs.</i> f/f control group, ANOVA or two-tailed student's <i>t</i> test).</p