High Sucrose, Fructose, and Glucose Diets and Glucocorticoid Dysregulation in Rats

Approximately two-thirds of U.S. adults are overweight or obese and the prevalence of overweight in children has tripled since 1980. Intake of added sugars has also increased. The etiology of obesity remains unclear and the role of glucocorticoids in obesity is one area of ambiguity. The enzyme 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD-1) interconverts active and inactive glucocorticoid, thereby regulating intracellular glucocorticoids. Dysregulation of 11beta-HSD-1 in liver and adipose is characteristic of human and animal models of obesity. Hexose-6-phosphate dehydrogenase (H6PDH) is colocalized with 11beta-HSD-1 and determines the set point for 11beta-HSD-1 oxidoreductase activity. In a long-term (10 wk) study, rats given ad libitum access to 16% sucrose solution, chow, and water were fatter than controls, had increased 11beta-HSD-1 mRNA in adipose, suppressed 11beta-HSD-1 mRNA in liver, and increased H6PDH mRNA in both tissues. The primary research questions were as follows: Can high sugar diets induce glucocorticoid dysregulation in the absence of excess adiposity? Does sugar type matter? Energy intake, weight gain, and parameters of lipid and carbohydrate metabolism were measured. Rats were randomly assigned to either ad libitum access to chow and water only (control), or in addition to ad libitum access to either 16% sucrose, fructose, or glucose solution (n=16/gp). After 24h and 1 wk, eight rats per group were randomly selected for sacrifice. Daily caloric intakes among sugar-fed groups did not differ and were higher than the mean intake of the control group. Within 24h, fructose induced increased 11beta-HSD-1 message in mesenteric adipose and liver. Plasma TG and insulin were acutely increased in groups with fructose-containing diets only. All high sugar diets induced suppressed hepatic 11beta-HSD-1 mRNA and protein after 1 wk. Upregulation of H6PDH mRNA observed in response to long-term high sucrose diets may result from increased adiposity and not solely diet. High sugar diets, irrespective of sugar type, initiate glucocorticoid dysregulation in the absence of phenotypic changes associated with obesity. Sucrose, fructose, and glucose have distinct metabolic and endocrine responses. Fructose has the unique ability to induce glucocorticoid dysregulation in liver and adipose in 24h

Chronic Ingestion of (3R,3'R,6'R)-Lutein and (3R,3'R)-Zeaxanthin in Female Rhesus Macaque Primates

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries in individuals over the age of 65. High intake of the dietary carotenoids lutein (L) and zeaxanthin (Z) is believed to reduce the risk of AMD. This study investigated the effects of long-term supplementation of primates with high doses of L or Z, and their 1:1 combination, and whether high supplemental doses cause ocular toxicity. Eighteen female rhesus macaques were divided into 4 groups: control (n=3), L-treated (n=5, 9.34 mg/kg L and 0.66 mg/kg Z), Z-treated (n=5, 10 mg/kg Z), and L/Z-treated (n=5, L and Z each at 0.5 mg/kg). At 6 month intervals beginning at baseline, plasma samples were analyzed by HPLC for L, Z, and their metabolites. Carotenoid analysis of tissues, ocular examinations, and toxicity assays were performed. High-dose supplementation of primates with L or Z significantly increased plasma, and ocular and other tissue concentrations of these carotenoids and their metabolites in most cases. Supplementation with a 1:1 dose of L and Z increased plasma concentrations of these carotenoids after 6 months, but baseline and month 12 levels in plasma and ocular tissues were not significantly different. Supplementation of primates with L or Z at high doses does not cause ocular or kidney toxicity

Loss of habenular Prkar2a reduces hedonic eating and increases exercise motivation

The habenula (Hb) is a bilateral, evolutionarily conserved epithalamic structure connecting forebrain and midbrain structures that has gained attention for its roles in depression, addiction, rewards processing, and motivation. Of its 2 major subdivisions, the medial Hb (MHb) and lateral Hb (LHb), MHb circuitry and function are poorly understood relative to those of the LHb. Prkar2a codes for cAMP-dependent protein kinase (PKA) regulatory subunit IIα (RIIα), a component of the PKA holoenzyme at the center of one of the major cell-signaling pathways conserved across systems and species. Type 2 regulatory subunits (RIIα, RIIβ) determine the subcellular localization of PKA, and unlike other PKA subunits, Prkar2a has minimal brain expression except in the MHb. We previously showed that RIIα-knockout (RIIα-KO) mice resist diet-induced obesity. In the present study, we report that RIIα-KO mice have decreased consumption of palatable, “rewarding” foods and increased motivation for voluntary exercise. Prkar2a deficiency led to decreased habenular PKA enzymatic activity and impaired dendritic localization of PKA catalytic subunits in MHb neurons. Reexpression of Prkar2a in the Hb rescued this phenotype, confirming differential roles for Prkar2a in regulating the drives for palatable foods and voluntary exercise. Our findings show that in the MHb decreased PKA signaling and dendritic PKA activity decrease motivation for palatable foods, while enhancing the motivation for exercise, a desirable combination of behaviors

PRKACB variants in skeletal disease or adrenocortical hyperplasia: effects on protein kinase A

Genetic variants in components of the protein kinase A (PKA) enzyme have been associated with various defects and neoplasms in the context of Carney complex (CNC) and in isolated cases, such as in primary pigmented nodular adrenocortical disease (PPNAD), cortisol-producing adrenal adenomas (CPAs), and various cancers. PRKAR1A mutations have been found in subjects with impaired cAMP-dependent signaling and skeletal defects; bone tumors also develop in both humans and mice with Prkar1a abnormalities. We studied the PRKACB gene in 148 subjects with PPNAD and related disorders, who did not have other PKA-related defects and identified two subjects with possibly pathogenic PRKACB gene variants and unusual bone and endocrine phenotypes. The first presented with bone and other abnormalities, and carried a de novo c.858_860GAA (p.K286del) variant. The second subject carried the c.899 C>T (p.T300M) variant and had a PPNAD-like phenotype. Both variants are highly conserved in the PRKACB gene. In functional studies, the p.K286del variant affected PRKACB protein stability and led to increased PKA signaling. The p.T300M variant did not affect protein stability or response to cAMP and its pathogenicity remains uncertain. We conclude that PRKACB germline variants are uncommon but may be associated with phenotypes that resemble those of other PKA-related defects. However, detailed investigation of each variant is needed as PRKACB appears to be only rarely affected in these conditions, and variants such as p.T300M maybe proven to be clinically insignificant, whereas others (such as p.K286del) are clearly pathogenic and may lead to a novel skeletal syndrome phenotype