geranylgeranylacetone and Body-Weight

Geranylgeranylacetone (GGA) is a chaperon inducer that protects various types of cell and tissue against stress. We examined whether GGA modulated energy intake and expenditure under stressful conditions. After mice were untreated or treated orally with GGA (0.16 g per kg body weight per day) for 10 days, they were subjected to 2-h restraint stress once or once a day for 5 consecutive days. GGA administration did not affect corticosterone response to the stress. Restraint stress rapidly decreased plasma leptin levels in control mice. GGA significantly increased circulating leptin levels without changing food intake and prevented the stress-induced decline of circulating leptin. However GGA-treated mice significantly reduced food intake during the repeated stress, compared with control mice. GGA prevented the stress-induced decline of leptin mRNA and its protein levels in epidydimal adipose tissues. We also found that GGA decreased ghrelin mRNA expression in gastric mucosa before the stress, whereas GGA-treated mice recovered the ghrelin mRNA expression to the baseline level after the repeated stress. Leptin and ghrelin are now recognized as regulators of anxiety and depressive mood. Our results suggest that GGA may regulate food intake and relief stress-induced mood disturbance through regulating leptin and ghrelin secretions. J. Med. Invest. 65:103-109, February, 2018.

Topics: Animals; Body Weight; Diterpenes; Eating; Ghrelin; HSP70 Heat-Shock Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Stress, Psychological

We evaluated heat shock protein 70 (HSP70) changes in diabetes mellitus (DM) in a nonhuman primate model. To this end, two studies were conducted in DM vervet monkeys. 1) Normal control and streptozotocin-induced DM monkeys (Stz-DM) that were differentiated into moderately or poorly controlled DM by judicious insulin administration were evaluated. Liver was collected at 4, 8, 12, 16, and 20 wk after streptozotocin, exposed to ex vivo heat shock at 42°C, and immunoblotted for heat shock factor 1 (HSF1), HSP70, and phosphorylated HSF1. 2) Spontaneous DM monkeys that were not pharmacologically induced were included in a crossover study of the HSP70-inducing drug geranylgeranylacetone (GGA). GGA at 20 mg/kg was given for 14 days with a 6-wk washout period. Glucose tolerance testing and plasma and muscle HSP70 were the primary outcome measurements. In Stz-DM, hyperglycemia reduced hepatic HSP70 in a dose-dependent fashion. HSF1 was increased in livers of monkeys with Stz-DM, but responses to ex vivo heat shock were impaired vs. normal monkeys. Activation of HSF1 appears to be important, because the phosphorylation change with heat stress was nearly perfectly correlated with HSP70 increases. Impaired HSF1 activation was also seen in Stz-DM after chronic hyperglycemia (>12 wk). In naturally occurring DM, increased circulating HSP70 resulted in significantly improved glucose tolerance and significant, positive trends in other measurements of insulin resistance. No change in muscle HSP70 content was observed. We conclude that increasing HSP70, potentially through targeting hyperglycemia-related deficits in HSF1 induction and activation in the liver, is a potent and viable strategy to improve glucose tolerance.

Topics: Analysis of Variance; Animals; Body Weight; Chlorocebus aethiops; Diabetes Mellitus, Experimental; Diterpenes; DNA-Binding Proteins; Dose-Response Relationship, Drug; Female; Glucose Intolerance; Glycated Hemoglobin; Heat Shock Transcription Factors; Heat Stress Disorders; HSP70 Heat-Shock Proteins; Hyperglycemia; Lipid Metabolism; Liver; Male; Phosphorylation; Transcription Factors

Induction of heat shock protein (HSP)72 improves insulin resistance and obesity in diabetic animal models. Geranylgeranylacetone (GGA), known as an antiulcer drug, induces HSP72 and protects organs against several cellular stresses. This study investigated whether GGA administration would induce HSP72 in liver and render physiological protection against high-fat feeding in mice. A single and 4-wk oral administration of 200 mg/kg GGA was performed in high-fat diet (HFD)-fed mice. Metabolic parameters, cytokines, and gene expressions related to insulin signaling were evaluated. A single administration of GGA induced HSP72 in liver of normal chow-fed and HFD-fed mice. Insulin resistance after HFD was slightly ameliorated. Four weeks of GGA administration also increased HSP72 in liver and significantly improved insulin resistance and glucose homeostasis upon glucose challenge. Activation of c-jun NH₂-terminal kinase (JNK) was attenuated, and insulin signaling was improved in the liver of HFD mice. Visceral adiposity was decreased in GGA-treated mice, accompanied by reduced leptin and increased adiponectin levels. GGA can be a novel therapeutic approach to treat metabolic syndrome as well as type 2 diabetes by improving insulin signaling and reducing adiposity. These beneficial effects of GGA could be mediated through HSP72 induction and JNK inactivation in the liver.

Topics: Adiponectin; Animals; Area Under Curve; Blood Glucose; Body Weight; Diterpenes; Eating; Glucose Tolerance Test; HSP72 Heat-Shock Proteins; Insulin; Insulin Resistance; Intra-Abdominal Fat; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Signal Transduction

Geranylgeranylacetone (GGA) has recently been reported to have a protective effect against ischemic, injurious and apoptotic stress in several tissues. The aim of this study was to determine the effect of GGA on colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice. Colitis was induced by intrarectal instillation of TNBS in 50% ethanol in BALB/c mice. Survival, change in body weight and change in wet colon weight were assessed. Histological score in the colon was evaluated 5 days after TNBS treatment. The level of myeloperoxidase (MPO) activity in the colon was also determined. Immunohistochemistry for CD4 in the colon was performed. In addition, the level of heat shock protein (HSP) 70 in the colon was determined by Western blot analysis. Mice were orally treated with GGA (300 mg/kg) 2 h before and every other day after starting TNBS administration. Treatment with GGA markedly improved the survival rate, and reduced the loss of body weight and loss of wet colon weight in mice with TNBS-induced colitis. GGA also suppressed the increase in MPO activity and the number of CD4-positive cells infiltrating the colons of mice with TNBS-induced colitis. Furthermore, treatment with GGA remarkably up-regulated the expression of HSP70 in the colons of mice with TNBS-induced colitis. Our results provide further evidence that GGA has therapeutic potential for intestinal inflammation.

Topics: Animals; Body Weight; CD4-Positive T-Lymphocytes; Colitis; Diterpenes; HSP70 Heat-Shock Proteins; Male; Mice; Mice, Inbred BALB C; Organ Size; Peroxidase; Survival Rate; Trinitrobenzenesulfonic Acid

The protective effect of geranylgeranylacetone (GGA), an antiulcer drug, against the acute toxicity and teratogenicity produced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was examined in C57BL/6J mice. When mice were co-treated, GGA reduced the loss of body weight gain and lethality produced by TCDD but hepatomegaly and thymic atrophy were not improved. Additionally, no protective effect of GGA was observed in the formation of cleft palate and hydronephrosis in mouse fetuses caused by maternal exposure to TCDD. To clarify the reducing mechanism by GGA, the Hsp70.1 mRNA levels in liver and intestine were analyzed. However, it was difficult to explain the effect of GGA from the induction of Hsp70.1. GGA had also no effect on the induction of hepatic ethoxyresorufin O-deethylase activity by TCDD. These data suggest that GGA exhibits a protective effect against some forms of dioxin toxicity by a mechanism without involving inhibition of arylhydrocarbon receptor activation.

Topics: Abnormalities, Drug-Induced; Animals; Anti-Ulcer Agents; Body Weight; Diterpenes; Female; Gene Expression; HSP70 Heat-Shock Proteins; Kidney; Male; Mice; Mice, Inbred C57BL; Organ Size; Polychlorinated Dibenzodioxins; Pregnancy; Time Factors

We investigated the development of gastric damage and body weight (BW) loss in lateral hypothalamic area (LHA)-lesioned rats, measured 2 h and 1 and 3 days after the lesioning (experiment 1), as well as the effects of geranylgeranylacetone (GGA), a cytoprotective antiulcer agent, on these disorders (experiment 2). In experiment 1, BW of LHA-lesioned rats decreased throughout the 3-day experiment. In LHA-lesioned rats, gastric mucosal lesions appeared 1 day after lesioning in the glandular portion and persisted, whereas those in the rumenal portion appeared only after 3 days. Gastric transepithelial potential differences (PDs) of glandular portion began to decrease after 2 h and had decreased in both portions. Gastric acid output was increased transiently at 2 h but it was not high after 1 day and after 3 days was lower than that in sham-LHA-lesioned rats. In experiment 2, PDs of the rumenal decreased more in LHA-lesioned rats than in sham-LHA-lesioned rats pair fed to LHA-lesioned rats after 3 days. Three days of treatment with GGA (200 mg/kg ip) improved PDs of rumenal and glandular portions in LHA-lesioned rats and reduced lesions of the rumenal portion. Loss of BW in LHA-lesioned rats was significantly but not completely inhibited by GGA. These results indicate that disturbance to the gastric defensive mechanism plays an important role in the development of gastric lesions after LHA lesions and that the impairment of gastric functions may be a partial cause of the loss of BW in LHA-lesioned rats.

Topics: Animals; Anti-Ulcer Agents; Body Weight; Diterpenes; Feeding Behavior; Female; Gastric Acid; Gastric Mucosa; Hypothalamic Area, Lateral; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Weight Loss