Brain-derived neurotrophic factor, corticotropin-releasing factor, and hypothalamic neuronal histamine interact to regulate feeding behavior.

Brain-derived neurotrophic factor (BDNF), corticotropin-releasing factor (CRF), and hypothalamic neuronal histamine are anorexigenic substances within the hypothalamus. This study examined the interactions among BDNF, CRF, and histamine during the regulation of feeding behavior in rodents. Food intake was measured after treatment with BDNF, α-fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), or CRF antagonist. We measured food intake in wild-type mice and mice with targeted disruption of the histamine H1 receptor (H1KO mice) after central BDNF infusion. Furthermore, we investigated CRF content and histamine turnover in the hypothalamus after BDNF treatment, and conversely, BDNF content in the hypothalamus after histamine treatment. We used immunohistochemical staining for histamine H1 receptors (H1-R) in BDNF neurons. BDNF-induced feeding suppression was partially attenuated in rats pre-treated with FMH or a CRF antagonist, and in H1KO mice. BDNF treatment increased CRF content and histamine turnover in the hypothalamus. Histamine increased BDNF content in the hypothalamus. Immunohistochemical analysis revealed that H1-Rs were expressed on BDNF neurons in the ventromedial nucleus of the hypothalamus. These results indicate that CRF and hypothalamic neuronal histamine mediate the suppressive effects of BDNF on feeding behavior and body weight.

Nesfatin-1, corticotropin-releasing hormone, thyrotropin-releasing hormone, and neuronal histamine interact in the hypothalamus to regulate feeding behavior.

Nesfatin-1, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and hypothalamic neuronal histamine act as anorexigenics in the hypothalamus. We examined interactions among nesfatin-1, CRH, TRH, and histamine in the regulation of feeding behavior in rodents. We investigated whether the anorectic effect of nesfatin-1, α-fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), a CRH antagonist, or anti-TRH antibody affects the anorectic effect of nesfatin-1, whether nesfatin-1 increases CRH and TRH contents and histamine turnover in the hypothalamus, and whether histamine increases nesfatin-1 content in the hypothalamus. We also investigated whether nesfatin-1 decreases food intake in mice with targeted disruption of the histamine H1 receptor (H1KO mice) and if the H1 receptor (H1-R) co-localizes in nesfatin-1 neurons. Nesfatin-1-suppressed feeding was partially attenuated in rats administered with FMH, a CRH antagonist, or anti-TRH antibody, and in H1KO mice. Nesfatin-1 increased CRH and TRH levels and histamine turnover, whereas histamine increased nesfatin-1 in the hypothalamus. Immunohistochemical analysis revealed H1-R expression on nesfatin-1 neurons in the paraventricular nucleus of the hypothalamus. These results indicate that CRH, TRH, and hypothalamic neuronal histamine mediate the suppressive effects of nesfatin-1 on feeding behavior.

Effects of a nonnutritive sweetener on body adiposity and energy metabolism in mice with diet-induced obesity.

OBJECTIVE: Nonnutritive sweeteners (NNSs) have been studied in terms of their potential roles in type 2 diabetes, obesity, and related metabolic disorders. Several studies have suggested that NNSs have several specific effects on metabolism such as reduced postprandial hyperglycemia and insulin resistance. However, the detailed effects of NNSs on body adiposity and energy metabolism have not been fully elucidated. We investigated the effects of an NNS on energy metabolism in mice with diet-induced obesity (DIO). METHODS: DIO mice were divided into NNS-administered (4% NNS in drinking water), sucrose-administered (33% sucrose in drinking water), and control (normal water) groups. After supplementation for 4 weeks, metabolic parameters, including uncoupling protein (UCP) levels and energy expenditure, were assessed. RESULTS: Sucrose supplementation increased hyperglycemia, body adiposity, and body weight compared to the NNS-administered and control groups (P<0.05 for each). In addition, NNS supplementation decreased hyperglycemia compared to the sucrose-administered group (P<0.05). Interestingly, NNS supplementation increased body adiposity, which was accompanied by hyperinsulinemia, compared to controls (P<0.05 for each). NNS also increased leptin levels in white adipose tissue and triglyceride levels in tissues compared to controls (P<0.05 for each). Notably, compared to controls, NNS supplementation decreased the UCP1 level in brown adipose tissue and decreased O2 consumption in the dark phase. CONCLUSIONS: NNSs may be good sugar substitutes for people with hyperglycemia, but appear to influence energy metabolism in DIO mice.

The dipeptidyl peptidase-4 inhibitor des-fluoro-sitagliptin regulates brown adipose tissue uncoupling protein levels in mice with diet-induced obesity.

OBJECTIVE: Dipeptidyl peptidase (DPP)-4 is responsible for the degradation of several peptides that contain an alanine or proline at the penultimate position or position P1. DPP-4 inhibitors (DPP-4is) have protective effects against type-2 diabetes and several metabolic disorders. METHODS: In the present study, we examined the effects of des-fluoro-sitagliptin (DFS), a DDP-4i, on body adiposity and levels of peroxisome proliferator-activated receptor (PPAR)-α, PPAR-γ coactivator-1 (PGC-1), and uncoupling proteins (UCPs) in mice with diet-induced obesity. RESULTS: Treatment with DFS dose-dependently decreased the weight of white adipose tissue and serum levels of glucose, compared with controls, without influencing food intake (P<0.05). Additionally, DFS treatment increased the levels of PPAR-α, PGC-1, and UCPs in brown adipose tissue (BAT), and of PPAR-α and UCP3 in skeletal muscle (P<0.05). Furthermore, the effects on BAT PGC-1 and muscle PPAR-α levels were attenuated by treatment with the glucagon-like peptide 1 (GLP-1) antagonist exendin (9-39). Interestingly, hypothalamic levels of proopiomelanocortin (POMC) were increased by DFS treatment and the effects of DFS on PPAR-α, PGC-1, and UCP levels were attenuated in melanocortin (MC)-4 receptor-deficient mice. CONCLUSIONS: In conclusion, high-dose DFS appeared to regulate body adiposity and UCPs in mice with diet-induced obesity, at least partly through a GLP-1 and/or MC-4 pathway.

Effects of hydrophilic statins on renal tubular lipid accumulation in diet-induced obese mice.

Animal models of obesity show that lipid deposits can injure the kidneys,and there is evidence for the role of lipids in the development of chronic renal dis-ease (CKD). Statins exhibit a lipid-lowering effect that acts on both total cholesterol and triglyceride (TG) levels and pleiotropic effects including their ability to reduce inflammation and fibrosis. The purpose of the present study was to confirm whether obesity induced by a high-fat diet (HFD, 60% fat) promotes lipid accumulation in the tubulointerstitial and/or glomerular areas in the kidney, and whether treatment of several statins, pravastatin (30 mg/kg, p.o.), rosuvastatin (3 mg/kg, p.o.),pitavastatin (1 mg/kg, p.o.) and atorvastatin (10 mg/kg, p.o.), suppresses obesity-induced lipid accumulation. Using male C57Bl/6J mice, we examined parameters related to energy metabolism, lipid accumulation as well as macrophage infiltration in glomeruli and the tubulointerstitial area, and glomerular injury using nephrin and desmin expression. None of the statins affected body weight, glucose metabolism,serum TG and adiponectin levels, or serum inflammatory cytokine levels. However,all statins improved lipid accumulation in the proximal tubules, improved glomerular hypertrophy, increased nephrin expression and decreased desmin expression, compared to non-treated obese animals. Moreover, the reduction of proximal tubular lipid accumulation was greater with pravastatin and rosuvastatin treatment than with pitavastatin and atorvastatin treatment. We concluded that hydrophilic statins may be more effective for preventing lipid accumulation in renal tubules than lipophilic statins.

Spleen-derived interleukin-10 downregulates the severity of high-fat diet-induced non-alcoholic fatty pancreas disease.

Obesity is associated with systemic low-grade inflammation and is a risk factor for non-alcoholic fatty pancreas disease (NAFPD), but the molecular mechanisms of these associations are not clear. Interleukin (IL)-10, a potent anti-inflammatory cytokine, is released during acute pancreatitis and is known to limit inflammatory responses by downregulating the release of proinflammatory mediators. The origin of IL-10 that suppresses pancreatitis has not been investigated. Since obesity is known to reduce expression of proinflammatory cytokines in the spleen, we examined whether spleen-derived IL-10 regulates NAFPD caused by high-fat (HF) diet-induced obesity. The following investigations were performed: 1) IL-10 induction from spleen was examined in male mice fed a HF diet; 2) triglyceride content, expression of pro- and anti-inflammatory cytokines and infiltration of M1 and M2 macrophages were determined to evaluate ectopic fat accumulation and inflammatory responses in the pancreas of splenectomy (SPX)-treated mice fed HF diet; 3) exogenous IL-10 was systemically administered to SPX-treated obese mice and the resulting pathogenesis caused by SPX was assessed; and 4) IL-10 knockout (IL-10KO) mice were treated with SPX and ectopic fat deposition and inflammatory conditions in the pancreas were investigated. Obesity impaired the ability of the spleen to synthesize cytokines, including IL-10. SPX aggravated fat accumulation and inflammatory responses in the pancreas of HF diet-induced obese mice and these effects were inhibited by systemic administration of IL-10. Moreover, SPX had little effect on fat deposition and inflammatory responses in the pancreas of IL-10KO mice. Our findings indicate that obesity reduces IL-10 production by the spleen and that spleen-derived IL-10 may protect against the development of NAFPD.