Hypothalamic free fatty acid receptor-1 regulates whole-body energy balance.

OBJECTIVE: Free fatty acid receptor-1 (FFAR1) is a medium- and long-chain fatty acid sensing G protein-coupled receptor that is highly expressed in the hypothalamus. Here, we investigated the central role of FFAR1 on energy balance. METHODS: Central FFAR1 agonism and virogenic knockdown were performed in mice. Energy balance studies, infrared thermographic analysis of brown adipose tissue (BAT) and molecular analysis of the hypothalamus, BAT, white adipose tissue (WAT) and liver were carried out. RESULTS: Pharmacological stimulation of FFAR1, using central administration of its agonist TUG-905 in diet-induced obese mice, decreases body weight and is associated with increased energy expenditure, BAT thermogenesis and browning of subcutaneous WAT (sWAT), as well as reduced AMP-activated protein kinase (AMPK) levels, reduced inflammation, and decreased endoplasmic reticulum (ER) stress in the hypothalamus. As FFAR1 is expressed in distinct hypothalamic neuronal subpopulations, we used an AAV vector expressing a shRNA to specifically knockdown Ffar1 in proopiomelanocortin (POMC) neurons of the arcuate nucleus of the hypothalamus (ARC) of obese mice. Our data showed that knockdown of Ffar1 in POMC neurons promoted hyperphagia and body weight gain. In parallel, these mice developed hepatic insulin resistance and steatosis. CONCLUSIONS: FFAR1 emerges as a new hypothalamic nutrient sensor regulating whole body energy balance. Moreover, pharmacological activation of FFAR1 could provide a therapeutic advance in the management of obesity and its associated metabolic disorders.

Orally Induced Hyperthyroidism Regulates Hypothalamic AMP-Activated Protein Kinase.

Besides their direct effects on peripheral metabolic tissues, thyroid hormones (TH) act on the hypothalamus to modulate energy homeostasis. However, since most of the hypothalamic actions of TH have been addressed in studies with direct central administration, the estimation of the relative contribution of the central vs. peripheral effects in physiologic conditions of peripheral release (or administration) of TH remains unclear. In this study we used two different models of peripherally induced hyperthyroidism (i.e., T4 and T3 oral administration) to assess and compare the serum and hypothalamic TH status and relate them to the metabolic effects of the treatment. Peripheral TH treatment affected feeding behavior, overall growth, core body temperature, body composition, brown adipose tissue (BAT) morphology and uncoupling protein 1 (UCP1) levels and metabolic activity, white adipose tissue (WAT) browning and liver metabolism. This resulted in an increased overall uncoupling capacity and a shift of the lipid metabolism from WAT accumulation to BAT fueling. Both peripheral treatment protocols induced significant changes in TH concentrations within the hypothalamus, with T3 eliciting a downregulation of hypothalamic AMP-activated protein kinase (AMPK), supporting the existence of a central action of peripheral TH. Altogether, these data suggest that peripherally administered TH modulate energy balance by various mechanisms; they also provide a unifying vision of the centrally mediated and the direct local metabolic effect of TH in the context of hyperthyroidism.

Small extracellular vesicle-mediated targeting of hypothalamic AMPKα1 corrects obesity through BAT activation.

Current pharmacological therapies for treating obesity are of limited efficacy. Genetic ablation or loss of function of AMP-activated protein kinase alpha 1 (AMPKα1) in steroidogenic factor 1 (SF1) neurons of the ventromedial nucleus of the hypothalamus (VMH) induces feeding-independent resistance to obesity due to sympathetic activation of brown adipose tissue (BAT) thermogenesis. Here, we show that body weight of obese mice can be reduced by intravenous injection of small extracellular vesicles (sEVs) delivering a plasmid encoding an AMPKα1 dominant negative mutant (AMPKα1-DN) targeted to VMH-SF1 neurons. The beneficial effect of SF1-AMPKα1-DN-loaded sEVs is feeding-independent and involves sympathetic nerve activation and increased UCP1-dependent thermogenesis in BAT. Our results underscore the potential of sEVs to specifically target AMPK in hypothalamic neurons and introduce a broader strategy to manipulate body weight and reduce obesity.

Polyunsaturated fatty acid receptors, GPR40 and GPR120, are expressed in the hypothalamus and control energy homeostasis and inflammation.

BACKGROUND: The consumption of large amounts of dietary fats is one of the most important environmental factors contributing to the development of obesity and metabolic disorders. GPR120 and GPR40 are polyunsaturated fatty acid receptors that exert a number of systemic effects that are beneficial for metabolic and inflammatory diseases. Here, we evaluate the expression and potential role of hypothalamic GPR120 and GPR40 as targets for the treatment of obesity. METHODS: Male Swiss (6-weeks old), were fed with a high fat diet (HFD, 60% of kcal from fat) for 4 weeks. Next, mice underwent stereotaxic surgery to place an indwelling cannula into the right lateral ventricle. intracerebroventricular (icv)-cannulated mice were treated twice a day for 6 days with 2.0 µL saline or GPR40 and GPR120 agonists: GW9508, TUG1197, or TUG905 (2.0 µL, 1.0 mM). Food intake and body mass were measured during the treatment period. At the end of the experiment, the hypothalamus was collected for real-time PCR analysis. RESULTS: We show that both receptors are expressed in the hypothalamus; GPR120 is primarily present in microglia, whereas GPR40 is expressed in neurons. Upon intracerebroventricular treatment, GW9508, a non-specific agonist for both receptors, reduced energy efficiency and the expression of inflammatory genes in the hypothalamus. Reducing GPR120 hypothalamic expression using a lentivirus-based approach resulted in the loss of the anti-inflammatory effect of GW9508 and increased energy efficiency. Intracerebroventricular treatment with the GPR120- and GPR40-specific agonists TUG1197 and TUG905, respectively, resulted in milder effects than those produced by GW9508. CONCLUSIONS: GPR120 and GPR40 act in concert in the hypothalamus to reduce energy efficiency and regulate the inflammation associated with obesity. The combined activation of both receptors in the hypothalamus results in better metabolic outcomes than the isolated activation of either receptor alone.

Leptin, Neuroinflammation and Obesity.

Hypothalamic resistance to adipostatic actions of leptin is a hallmark of obesity. Studies have revealed that hypothalamic inflammation, triggered in response to the consumption of large amounts of dietary fat, is an important mechanism in the development of leptin resistance. In this chapter, we will review the work that paved the way linking neuroinflammation of the hypothalamus and defective leptin action in obesity.

Passiflora edulis peel intake improves insulin sensitivity, increasing incretins and hypothalamic satietogenic neuropeptide in rats on a high-fat diet.

OBJECTIVE: This study aimed to investigate the effect of Passiflora edulis peel flour (PEPF) intake on hypothalamic neuropeptides messenger RNA expression, insulin sensitivity, and other metabolic parameters in Sprague-Dawley rats fed a high-fat (HF) diet. METHODS: Sprague-Dawley rats were divided in 3 groups: a control group, fed on a normal fat diet; a HF group, fed on a high-fat diet (35% fat [w/w]); and a high-fat Passiflora flour (HFPF) group, fed on a HF diet containing PEPF. The rats from the HFPF group as well as the HF group were kept on an HF diet for the first 4 wk to induce metabolic conditions related to obesity. Then the HFPF group was switched to a HF diet containing PEPF for additional 6 wk. Other groups were kept on normal-fat and HF diet without addition of PEPF during the whole period of experiment. The glucose tolerance and insulin sensitivity were evaluated through the glucose tolerance test (GTT) and the insulin tolerance test (ITT). Gut hormones and adipokines were measured through an immunoassay. The hypothalamic neuropeptides expression was assessed by real-time polymerase chain reaction. RESULTS: The PEPF intake increased the hypothalamic cocaine- and amphetamine-regulated transcript expression (CART) (P < 0.05), counteracted cumulative body weight gain (P < 0.001), decreased adiposity (P < 0.05) and leptin level (P < 0.01), whereas increased adiponectin (P < 0.01), glucose-dependent insulinotropic polypeptide (P < 0.01), and glucagon-like peptide-1 (GLP-1) (P < 0.001) improved the insulin sensitivity in diet-induced obesity rats by increasing the kITT (glucose disappearance rate) (P < 0.01), which was calculated during the ITT. Other gut hormones (peptide tyrosine tyrosine, pancreatic polypeptide, and amylin) and interleukins (IL) (IL-6, tumor necrosis factor-α, IL-1ß, and monocyte chemoattractant protein-1) were not changed by the PEPF intake. CONCLUSION: Our findings provide a further understanding of how the PEPF works as a dietary component to improve glucose homeostasis and demonstrate a molecular mechanism that may increase satiety by PEPF in diet-induced obesity.

Freeze-dried jaboticaba peel powder improves insulin sensitivity in high-fat-fed mice.

The peel of the native Brazilian fruit jaboticaba is rich in anthocyanins, which are known for their anti-obesity effects in animal models. The aim of the present study was to evaluate the effects of freeze-dried jaboticaba peel powder (FDJPP) on a number of metabolic parameters in a model of diet-induced obesity. Mice (n 8 per group) were initially fed on a high-fat diet (HFD, 35% w/w) for 4 weeks and then switched to a HFD supplemented with FDJPP (1, 2 or 4% w/w) for an additional 6 weeks. Energy intake, weight loss, glucose tolerance, insulin resistance and lipid profile were determined, and the results were evaluated using ANOVA and Tukey's tests. The FDJPP exerted no protective effect on HFD-induced weight gain, hyperleptinaemia and glucose intolerance. However, the supplementation was effective to reduce insulin resistance, as evidenced in the insulin tolerance test, and subsequently confirmed by improved signal transduction through the insulin receptor/insulin receptor substrate-1/Akt/forkhead box protein pathway and by the attenuation of HFD-induced inflammation in the liver, verified by lower expressions of IL-1b and IL-6 and decreased phosphorylated IkB-a protein levels in all jaboticaba-treated mice. These results suggest that FDJPP may exert a protective role against obesity-associated insulin resistance.

In vivo antimutagenic properties of transgenic and conventional soybeans.

The goal of the this study was to evaluate the mutagenic/antimutagenic effects of conventional (BRS133) and transgenic (BRS 245 RR) soybeans (CS and TS, respectively) in vivo using the bone marrow micronucleus (MN) test, histopathological analysis, chromosome aberration test (CAT), and mitotic index (MI) determination. Six-week-old male Swiss mice were fed with pelleted commercial diet mixed with CS or TS at 10% or 20%. Two experimental designs (MN and CAT) were conducted simultaneously with 10 groups each during a 15-day period. Animals were treated with pelleted commercial diet, CS (10% or 20%), or TS (10% or 20%), and on day 14 they also received cyclophosphamide (CP) (50 mg/kg i.p.). The 10% and 20% CS and TS diets did not significantly decrease the frequencies of micronucleated polychromatic erythrocytes in bone marrow induced by CP. However, the CAT indicated that the 10% and 20% CS diets significantly (P < .05) protected nucleated bone marrow cells against chemical-induced mutagenesis and also produced a significant (P < .05) decrease in the total percentage of spontaneous aberrations. Among the treatments with TS, only the 10% TS diet reduced the percentage of total aberrations induced by CP. The results also indicated that the treatment with 20% TS alone significantly (P < .05) decreased the MI, indicating cytotoxic effects related to the treatment. Taken together, our results suggest that, under the tested conditions, TS and CS have antimutagenic properties and are not toxic.