Fatty acid amide hydrolase ablation promotes ectopic lipid storage and insulin resistance due to centrally mediated hypothyroidism

Abstract

Fatty acid amide hydrolase (FAAH) knockout mice are prone to excess energy storage and adiposity, whereas mutations in FAAH are associated with obesity in humans. However, the molecular mechanism by which FAAH affects energy expenditure (EE) remains unknown. Here we show that reduced energy expenditure in FAAH −/− mice could be attributed to decreased circulating triiodothyronine and thyroxine concentrations secondary to reduced mRNA expression of both pituitary thyroid-stimulating hormone and hypothalamic thyrotropin-releasing hormone. These reductions in the hypothalamic-pituitary-thyroid axis were associated with activation of hypothalamic peroxisome proliferating-activated receptor γ (PPARγ), and increased hypothalamic deiodinase 2 expression. Infusion of NAEs (anandamide and palmitoylethanolamide) recapitulated increases in PPARγ-mediated decreases in EE. FAAH −/− mice were also prone to diet-induced hepatic insulin resistance, which could be attributed to increased hepatic diacylglycerol content and protein kinase Cε activation. Our data indicate that FAAH deletion, and the resulting increases in NAEs, predispose mice to ectopic lipid storage and hepatic insulin resistance by promoting centrally mediated hypothyroidism. NAPEs) and N-acylethanolamines (NAEs) are nutrient-regulated lipokines that affect energy homeostasis through regulation of satiety and energy storage, selectively increasing in abundance with high-fat diet (HFD) feeding (1-7). NAPEs are hydrolyzed to produce diverse NAE species, which act as ligands for cannabinoid receptor 1 (CB1), G protein-coupled receptor 119 (GPR119), GPR55, peroxisome proliferating-activated receptor α (PPARα), and transient receptor potential cation channel subfamily V member 1 to affect appetite, gut hormone release, anxiety, and inflammation (8-12). Fatty acid amide hydrolase (FAAH) is the major enzyme responsible for the degradation of NAEs. An integral membrane protein, FAAH is expressed predominantly in the brain, liver, kidney, and intestine (13,14). Mice lacking FAAH (FAAH −/− mice) have increased body weight after 12 wk of HFD feeding, independent of food intake (7) and decreased energy expenditure (EE) (15). Furthermore, SNPs in the FAAH gene correlate with obesity in humans (16,17).NAEs are lipid-signaling molecules that have diverse physiological effects. Anandamide (AEA), an endocannabinoid and an endogenous ligand of CB1, is the most well-studied NAE (11). Inhibition of CB1 promotes EE, leading to decreased body weight in HFD-fed mice (18). In addition, treatment with the CB1 inhibitor rimonabant increases oxygen consumption in isolated soleus muscle of obese mice (5).Because FAAH is expressed in metabolically active tissues and may be a genetic cause of obesity in humans, we investigated EE and tissue-specific insulin sensitivity in FAAH −/− and FAAH +/+ mice. To do so, we measured the expression of genes and hormones known to regulate EE, including PPARγ, proopiomelanocortin (POMC), and thyroid hormones. Here we show that FAAH regulates EE via the ac...

Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesity

“…Of note, our finding that elevations of NAEs in the liver corresponded with slightly increased resting energy expenditure contrasts with a recent study that found decreased resting energy expenditure when NAE levels were elevated systematically by genetic ablation of fatty acid amide hydrolase or by subcutaneous infusion of synthetic NAE (63). In that study, NAE levels were significantly elevated both in plasma and in the brain.…”

“…The elevated brain NAE levels corresponded with reduced mRNA expression of thyrotropin-releasing hormone in the hypothalamus and thyroidstimulating hormone in the pituitary gland and with increased mRNA expression of deiodinase 2 in the hypothalamus. These changes resulted in lower circulating levels of triodothyronine (T 3 ) and thyroxine (T 4 ) and therefore decreased energy expenditure (63). Thus, the failure of the bacterially synthesized NAPE metabolites to reach the systemic circulation and the CNS may be somewhat beneficial, as this minimizes the likelihood that they will induce counterregulatory effects on energy expenditure in the CNS.…”

Palmitoylethanolamide improves colon inflammation through an enteric glia/toll like receptor 4-dependent PPAR-α activation

“…Animal care was in compliance with the IASP and European Community (EC L358/1 18/12/86) guidelines on the use and protection of animals in experimental research. Animals were randomly divided into the following groups (n=10 each): non-colitic control group; colitic group; colitic groups receiving daily PEA 2, 10 or 50 mg/kg, respectively25 26; colitic group receiving daily PEA (10 mg/kg) and selective PPARα antagonist MK866 (10 mg/kg); colitic group receiving daily PEA and selective PPARγ antagonist GW9662 (1 mg/kg); internal control colitic group receiving daily PPARα or PPARγ antagonist, respectively27; non-colitic group receiving daily PEA 10 mg/kg (as drug internal control). Colitis was induced by administrating 4% DSS (MP Biomedicals, Solon, Ohio, USA) in drinking water for six consecutive days, as described in figure 1A.…”

Endocannabinoid Regulation of Neuroendocrine Systems

“…Although this has not been demonstrated in the hypothalamus, CRH in the PVN is a known regulator of feeding behavior and may work through a similar mechanism to alter feeding behavior by regulating eCB levels in the PVN. Interestingly, FAAH knockout mice display reduced energy expenditure (Brown et al, 2012), which indicates that FAAH may play a direct role in energy metabolism. Pregastric neurons in the PVN that control gastric motility are subject to control by eCBs, which is likely to be mediated by AEA since both CB 1 and TRPV1 receptors are implicated (Boychuk, Zsombok, Tasker, & Smith, 2013) and AEA targets both receptors, whereas 2-AG binds only to CB 1 receptors.…”