Terence T. Yen

Obesity, diabetes, and neoplasia in yellow A(vy)/- mice: ectopic expression of the agouti gene.

The viable yellow Avy mutation results in a mottled yellow mouse that is obese, slightly larger than its nonyellow sibs, and more susceptible to tumor formation in those tissues sensitized by the strain genome. The mutation exhibits variable expressivity resulting in a continuum of coat color phenotypes, from clear yellow to pseudoagouti. The mouse agouti protein is a paracrine signaling molecule that induces hair follicle melanocytes to switch from the synthesis of black pigment to yellow pigment. Molecular cloning studies indicate that the obesity and growth effects of the Avy mutation result from ectopic expression of the normal agouti gene product. This review seeks to summarize the current state of knowledge regarding the obesity, stimulation of somatic growth, and enhancement of tumor formation caused by the Avy mutation, and to interpret these pleiotropic effects in terms of the normal function of the agouti protein.—Yen, T. T., Gill, A. M., Frigeri, L. G., Barsh, G. S., and Wolff, G. L. Obesity, diabetes, and neoplasia in yellow Avy/‐ mice: ectopic expression of the agouti gene. FASEB J. 8: 479‐488; 1994.

Triacylglycerol contents and in vivo lipogenesis of ob/ob, db/db and Avy/a mice

The triacylglycerol content and the in vivo lipogenesis rates of the liver and the carcass of 12 groups of mice were studied. They were mice of three strains and affected by mutations at three loci: C57BL/6J-ob/ob and normal mice; C57BL/KsJ-db/db and normal mice; and VY/WfL-Avy/a and normal mice. Each type of mice was studied at two body weight levels, before and after the mutants became grossly obese. It was found that the C57BL/6J-ob/ob and the C57BL/KsJ-db/db mice had the characteristics of juvenile type obesity. They had higher lipogenesis rates and accumulated more triacylglycerol when they were young. They gained weight rapidly mainly due to the accumulation of more triacylglycerol as they matured. Their total triacylglycerol content could reach 50% of their body weight. At maturity, their lipogenesis rates had decreased to normal. In contrast, the VY/WfL-Avy/a mice had the characteristics of maturity-onset type obesity. When they were young, they did not have higher lipogenesis rates and had only a moderate amount of triacylglycerol stored. They did not gain weight rapidly as they matured. However, when they reached maturity, their lipogenesis rate did not decrease. Their body triacylglycerol content was about 25% of their weight.

Effects of ciglitazone on endogenous plasma islet amyloid polypeptide and insulin sensitivity in obese-diabetic viable yellow mice

The role of islet amyloid polypeptide, also known as amylin, in insulin resistance and in the etiology of diabetes has been a subject of debate. Increased plasma amylin levels have been observed in both obese and type II diabetic patients. However, data on endogenous amylin levels with relation to pharmacological interventions have not been reported. In this study, chronic treatment of obese-diabetic viable yellow mice with ciglitazone was shown to significantly alter various parameters. Blood glucose and plasma insulin, triglyceride, and amylin levels were reduced and glucose tolerance in the presence of exogenous insulin was improved. Insulin/amylin ratios which were found to be significantly elevated in diabetic mice as compared to normal controls, were decreased after ciglitazone treatment. However, observed decreases in both amylin and insulin concentrations due to ciglitazone treatment and their subsequent increases upon withdrawal of treatment were correlated, suggesting cosecretion.

Pergolide: A potent dopaminergic antihypertensive

Abstract Pergolide, a potent centrally acting dopamine agonist, lowered both blood pressure and heart rate of spontaneously hypertensive rats and normotensive rats. Its blood pressure-lowering activity in both types of rats was more potent than that of lergotrile, a weaker dopamine agonist. The parallelism between the antihypertensive activity and the dopaminergic potency of the two compounds and the complete antagonism of the antihypertensive activity of pergolide by haloperidol, a dopaminergic blocker, indicate the involvement of dopaminergic mechanisms in maintaining the homeostasis of blood pressure and perhaps in the pathology of hypertension such as that in spontaneously hypertensive rats.

Pancreatic Islet Cells in Preobese Yellow Avy/- Mice: Relation to Adult Hyperinsulinemia and Obesity:

Abstract Plasma insulin levels in yellow Avy /- mice begin to increase before the animals are overtly obese. Are the elevated insulin levels in yellow mice primary or secondary to the subsequent obesity? Elevated blood insulin levels in young preobese mice, due to synthesis and release of insulin by increased number of β cells, would stimulate lipogenesis, resulting in excess lipid deposition and subsequent peripheral insulin resistance. Examination of this possibility was the objective of this study. The β, α, and δ cells in the pancreata of 7-, 14-, and 21-day-old male yellow Avy/A and agouti A/a (BALB/c x VY)F1 hybrid mice were counted with immunohistochemical/morphometric techniques. The insulin and glucagon concentrations in pancreata from male and female mice of the same ages and genotypes were also assayed. In the 21-day-old male mice, the mean number of β cells/pancreas was significantly greater in the yellow mice than in the agouti mice; however, insulin content and body weight were the same. This suggests that increased β cell proliferation in yellow mice precedes any detectable genotype-specific increase in pancreatic insulin content or body weight.

Antihypertensive effects of fluoxetine and L-5-hydroxytryptophan in rats.

Abstract The combination of fluoxetine (10 mg/kg) and L-5-hydroxytryptophan (5-HTP) (10 mg/kg) significantly lowered blood pressure in spontaneously hypertensive rats and in rats made hypertensive by treatment with deoxycorticosterone (DOCA) and saline. Fluoxetine alone also had a significant effect on blood pressure in DOCA hypertensive rats, but not as great an effect as the combination. Since fluoxetine is an inhibitor of serotonin reuptake and 5-HTP is the serotonin precursor, the antihypertensive effect of this drug combination strengthens previous evidence that serotonin neurons have a role in the central regulation of blood pressure.

Dexamethasone-Induced Hyperglycemia in Obese Avy/a (Viable Yellow) Female Mice Entails Preferential Induction of a Hepatic Estrogen Sulfotransferase

Sex steroid sulfotransferases (ST) sulfurylate and thus inactivate estrogens or androgens, producing an androgenized or estrogenized state in the liver. The expression of diabetes in a number of animal models is sexually dimorphic and has been associated with steroidal states. Although the viable yellow (Avy) mutation produces an insulin-resistant obesity syndrome in mice of both sexes, only males develop chronic hyperglycemia. Hyperglycemia was rapidly induced in Avy/a females by dexamethasone (dex). This treatment completely suppressed both endogenous plasma corticosterone and hepatic corticosterone-binding globulin (CBG) mRNA within 24 h. Hyperglycemia in dex-implanted Avy/a females was accompanied by aberrant shifts in hepatic androgen/estrogen balance. This was effected by induction of estrogen sulfotransferase (EST) mRNA together with a > 10-fold increase in enzymatic activity. Similar dex-induced increases in androgen ST or phenol ST were not observed. Prior implantation of estrogen prevented development of hyperglycemia. The time-dependent spontaneous reversal of dex-induced hyperglycemia correlated with re-expression of CBG mRNA transcripts and reduced levels of EST transcripts and enzyme activity. Although dex-induced hyperglycemia was limited to Avy/a females, dex elicited hyperinsulinemia in lean α/α control mice of both sexes and exacerbated constitutive hyperinsulinemia in Avy/a males and females. In summary, dex-induced hyperglycemia in Avy/a females was associated with increased catabolism of hepatic estrogens mediated by induction of EST.

The response of 'obese' (ob/ob) and 'diabetic' (db/db) mice to treatments that influence body temperature.

Abstract 1. 1. Rectal temperatures were measured in “obese” ( ob/ob ) and “diabetic” ( db/db ) mice compared to nonobese and nondiabetic mice in the C57BL/6J and C57BL/KsJ strains, respectively, after treatments that influence body temperature. Neither ob/ob nor db/db mice maintained their body temperature in a 4°C environment as well as did the control mice; ob/ob mice but not db/db mice did maintain their body temperature normally in 36°C. 2. 2. There were strain differences in the response of these mice to a hypothermic agent, apomorphine. Apomorphine caused a larger decrease in body temperature in the C57BL/6J mice than in C57BL/KsJ mice. The ob/ob mice and particularly the db/db mice showed less of a response to hypothermie drugs (apomorphine, tremorine and amphetamine in a 4°C environment) than did controls. In contrast, the hyperthermic response to amphetamine (at room temperature) was normal in both db/db and ob/ob mice. 3. 3. The abnormalities in thermoregulation that are common to db/db and ob/ob mice (lower basal body temperature, sensitivity to cold stress but not hypothermie drugs) might be due in some way to the obesity of both groups of mice. In addition, however, the db/db mice seem to be different from ob/ob mice in their greater sensitivity to cold stress and to heat stress and their lesser sensitivity to hypothermie drugs; this difference may suggest a specific thermoregulatory defect in the db/db mice.

Ephedrine reduces weight of viable yellow obese mice (Avy/a)

Abstract Ephedrine administered subcutaneously or in the diet reduces the weight of viable yellow obese mice ( A vy / a ) and normal mice. The compound has some appetite-suppression activity; however, reduced food consumption could not account for all of the weight loss. Ephedrine did not affect lipogenesis or lipolysis acutely. The major portion of the weight loss was due to the loss of triacylglycerol. The rectal temperature of long-term treated A vy / a mice was elevated suggesting that ephedrine may alter energy metabolism.

Lowering of blood pressure by direct- and indirect-acting serotonin agonists in spontaneously hypertensive rats.

1-(m-Trifluoromethylphenyl)piperazine, a serotonin agonist, lowered blood pressure in spontaneously hypertensive rats (SHR) at doses of 2 to 10 mg/kg s.c. A structurally related compound lacking serotonin agonist activity, 4-(m-trifluoromethylphenyl)piperidine, was ineffective. Quipazine, another serotonin agonist, lowered blood pressure in SHR at doses of 0.1 to 2 mg/kg s.c. Fenfluramine, a serotonin-releasing drug, lowered blood pressure in SHR at doses of 2 and 5 mg/kg s.c. Metergoline (3 mg/kg s.c.), a serotonin antagonist, elevated blood pressure and prevented the decrease by all of the above agents. These findings are consistent with the view that enhancement of central serotonergic function lowers blood pressure in SHR.