Biomedical subjects

M B Zemel

Publications and source records attributed to M B Zemel.

At least 19 recordsLinked to original sources

PubMed2006

Dietary calcium regulates ROS production in aP2-agouti transgenic mice on high-fat/high-sucrose diets.

OBJECTIVE: We have previously demonstrated that 1alpha, 25(OH)2D3 promotes adipocyte reactive oxygen species (ROS) production. We have now evaluated whether decreasing 1alpha, 25(OH)2D3 levels by increasing dietary calcium will decrease oxidative stress in vivo. METHODS: We fed low-calcium (0.4% Ca) and high-calcium (1.2% Ca from CaCO3) obesity-promoting (high sucrose/high fat) diets to aP2-agouti transgenic mice and assessed regulation of ROS production in adipose tissue and skeletal muscle. RESULTS: Mice on the high-calcium diet gained 50% of the body weight (P=0.04) and fat (P<0.001) as mice on the low-calcium diet (0.4% Ca). The high-calcium diet significantly reduced adipose intracellular ROS production by 64 and 18% (P<0.001) and inhibited adipose tissue nicotinamide adenine dinucleotide phosphate oxidase expression by 49% (P=0.012) and 63% (P=0.05) in visceral and subcutaneous adipose tissue, respectively. Adipocyte intracellular calcium ([Ca2+]i) levels were suppressed in mice on the high-calcium diet by 73-80% (P<0.001). The high-calcium diet also induced 367 and 191% increases in adipose mitochondrial uncoupling protein 2 (UCP2) expression (P<0.001) in visceral and subcutaneous adipose tissue, respectively. The pattern of UCP3 expression and indices of ROS production in skeletal muscle were consistent with those in adipose tissue. The high-calcium diet also suppressed 11beta-hydroxysteroid dehydrogenase (11beta-HSD) expression in visceral adipose tissue by 39% (P=0.034). 11beta-HSD expression was markedly higher in visceral vs subcutaneous adipose tissue in mice on the low-calcium diet (P=0.034), whereas no difference was observed between the fat depots in mice on the high-calcium diet. CONCLUSION: These data support a potential role for dietary calcium in the regulation of obesity-induced oxidative stress.

Adipocytes↗

PubMed2005

Dairy augmentation of total and central fat loss in obese subjects.

BACKGROUND AND OBJECTIVE: We have previously demonstrated an antiobesity effect of dietary Ca; this is largely mediated by Ca suppression of calcitriol levels, resulting in reduced adipocyte intracellular Ca2+ and, consequently, a coordinated increase in lipid utilization and decrease in lipogenesis. Notably, dairy Ca is markedly more effective than other Ca sources. DESIGN: Obese subjects were placed on balanced deficit (-500 kcal/day) diets and randomized to control (400-500 mg Ca/day; n = 16) or yogurt (1100 mg Ca/day; n = 18) treatments for 12 weeks. Dietary macronutrients and fiber were held constant at the US average. MEASUREMENTS: Body weight, body fat and fat distribution (by dual-energy X-ray absorptiometry), blood pressure and circulating lipids were measured at baseline and after 12 weeks of intervention. RESULTS: Fat loss was markedly increased on the yogurt diet (-4.43+/-0.47 vs -2.75+/-0.73 kg in yogurt and control groups; P<0.005) while lean tissue loss was reduced by 31% on the yogurt diet. Trunk fat loss was augmented by 81% on the yogurt vs control diet (P<0.001), and this was reflected in a markedly greater reduction in waist circumference (-3.99+/-0.48 vs -0.58+/-1.04 cm, P<0.001). Further, the fraction of fat lost from the trunk was higher on the yogurt diet vs control (P<0.005). CONCLUSION: Isocaloric substitution of yogurt for other foods significantly augments fat loss and reduces central adiposity during energy restriction..

Adolescent↗

PubMed2001

1alpha,25-Dihydroxyvitamin D3 modulates human adipocyte metabolism via nongenomic action.

We reported recently that suppression of the renal 1alpha,25-dihyroxyvitamin D3 (1lpha,25-(OH)2-D3) production in aP2-agouti transgenic mice by increasing dietary calcium decreases adipocyte intracellular Ca2+ ([Ca2+]i), stimulates lipolysis, inhibits lipogenesis, and reduces adiposity. However, it was not clear whether this modulation of adipocyte metabolism by dietary calcium is a direct effect of inhibition of 1alpha,25-(OH)2-D3-induced [Ca2+]i. Accordingly, we have now evaluated the direct role of 1alpha,25-(OH)2-D3. Human adipocytes exhibited a 1alpha,25-(OH)2-D3 dose-responsive (1-50 nM) increase in [Ca2+]i (P<0.01). This action was mimicked by 1alpha,25-dihyroxylumisterol3 (1alpha,25-(OH)2-lumisterol3) (P<0.001), a specific agonist for a putative membrane vitamin D receptor (mVDR), and completely prevented by 1b,25-dihydroxyvitamin D3 (1beta,25-(OH)2-D3), a specific antagonist for the mVDR. Similarly, 1alpha,25-(OH)2-D3 (5 nM) caused 50%-100% increases in adipocyte fatty acid synthase (FAS) expression and activity (P<0.02), a 61% increase in glycerol-3-phosphate dehydrogenase (GPDH) activity (P<0.01), and an 80% inhibition of isoproterenol-stimulated lipolysis (P<0.001), whereas 1beta,25-(OH)2-D3 completely blocked all these effects. Notably, 1alpha,25-(OH)2-lumisterol3 exerted more potent effects in modulating adipocyte lipid metabolism, with 2.5- to 3.0-fold increases in FAS expression and activity (P<0.001) and a threefold increase in GPDH activity (P<0.001). Also 1alpha,25-(OH)2-lumisterol3 was approximately twice as potent in inhibiting basal lipolysis (P<0.025), whereas 1beta,25-(OH)2-D3 completely blocked all these effects. These data suggest that 1alpha,25-(OH)2-D3 modulates adipocyte Ca2+ signaling and, consequently, exerts a coordinated control over lipogenesis and lipolysis. Thus, a direct inhibition of 1alpha,25-(OH)2-D3-induced [Ca2+]i may contribute to an anti-obesity effect of dietary calcium, and the mVDR may represent an important target for obesity.

Adipocytes↗

PubMed2001

Mechanism of intracellular calcium ([Ca2+]i) inhibition of lipolysis in human adipocytes.

We investigated the mechanisms responsible for the anti-lipolytic effect of intracellular Ca2+ ([Ca2+]i) in human adipocytes. Increasing [Ca2+]i inhibited lipolysis induced by b-adrenergic receptor activation, A1 adenosine receptor inhibition, adenylate cyclase activation, and phosphodiesterase (PDE) inhibition, as well as by a hydrolyzable cAMP analog, but not by a nonhydrolyzable cAMP analog. This finding indicates that the anti-lipolytic effect of [Ca2+]i may be mediated by the activation of adipocyte PDE. Consistent with this theory, [Ca2+]i inhibition of isoproterenol-stimulated lipolysis was reversed completely by the nonselective PDE inhibitor isobutyl methylxanthine and also by the selective PDE 3B inhibitor cilostamide, but not by selective PDE 1 and 4 inhibitors. In addition, phosphatidylinositol-3 kinase inhibition with wortmannin completely prevented insulin's anti-lipolytic effect but only minimally blocked [Ca2+]i's effect, which suggests that [Ca2+]i and insulin may activate PDE 3B via different mechanisms. In contrast, the antilipolytic effect of [Ca2+]i was not affected by inhibitors of calmodulin, Ca2+/calmodulin-dependent kinase, protein phosphatase 2B, and protein kinase C. Finally, [Ca2+]i inhibited significantly isoproterenol-stimulated increases in cAMP levels and hormone-sensitive lipase phosphorylation in human adipocytes. In conclusion, increasing [Ca2+]i exerts an antilipolytic effect mainly by activation of PDE, leading to a decrease in cAMP and HSL phosphorylation and, consequently, inhibition of lipolysis.

1-Methyl-3-isobutylxanthine↗

PubMed2001

Calcium modulation of hypertension and obesity: mechanisms and implications.

Regulation of intracellular calcium plays a key role in hypertension and obesity. Dysregulation of calcium homeostasis appears to be a fundamental factor linking these conditions. Regulation of intracellular calcium in key disease-related target tissues by calcitrophic hormones provides the opportunity to modulate disease risk with dietary calcium. Overall, sub-optimal calcium intakes contribute to the etiology of salt-sensitivity and hypertension. High salt diets exert a calciuretic effect, serving to exacerbate the physiological consequences of sub-optimal calcium diets. Among these are increases in 1,25-dihydroxyvitamin D, which increases vascular smooth muscle intracellular calcium, thereby increasing peripheral vascular resistance and blood pressure. Dietary calcium reduces blood pressure in large part via suppression of 1,25-dihydroxyvitamin D, thereby normalizing intracellular calcium. The practical relevance of this approach has been confirmed in the DASH (Dietary Approaches to Stop Hypertension) trial, which demonstrated that increasing low-fat dairy product and fruit and vegetable consumption exerted profound blood pressure-lowering effects. The magnitude of this effect among hypertensives was comparable to that typically found in pharmacological trials of mild hypertension. 1,25-dihydroxyvitamin D also stimulates calcium influx in human adipocytes, resulting in stimulation of lipogenesis, inhibition of lipolysis and expansion of triglyceride stores. Accordingly, suppression of 1,25-dihydroxyvitamin D by dietary calcium has been identified as a target, which may contribute to the prevention and management of obesity. Indeed, laboratory, clinical and population data all indicate a significant anti-obesity effect of dietary calcium, although large-scale prospective clinical trials have not yet been conducted to definitively demonstrate the scope of this effect. Thus, available evidence indicates that increasing dietary calcium intakes may result in reductions in fat mass as well as in blood pressure.

Adipose Tissue↗

PubMed2001

Agouti signaling protein stimulates islet amyloid polypeptide (amylin) secretion in pancreatic beta-cells.

Ectopic overexpression of the murine agouti gene results in yellow coat color, obesity, hyperinsulinemia, and type II diabetes. We have shown the human homologue of agouti (agouti signaling protein; ASP) to regulate human adipocyte metabolism and lipid storage via a Ca(2+)-dependent mechanism. We have also demonstrated agouti expression in human pancreas, and that ASP stimulates insulin release via a similar Ca(2+)-dependent mechanism. Plasma amylin is also elevated in agouti mutant mice. Amylin is cosecreted with insulin from beta-cells, and overexpression of human amylin in beta-cells in yellow agouti mutant mice resulted in accelerated pancreatic amyloid deposition, severely impaired beta-cell function, and a diabetic phenotype. We report here that ASP stimulates amylin release in both the HIT-T15 beta-cell line and human pancreatic islets in the presence of a wide range of glucose concentrations (0-16.7 mmol/L), similar to its effect on insulin release; this effect was blocked by 30 mumol/L nitrendipine, confirming a Ca(2+)-dependent mechanism. Accordingly, ASP stimulation of amylin release may serve as a compensatory system to regulate blood glucose in yellow agouti mutants.

Agouti Signaling Protein↗

PubMed2000

Effects of dietary calcium on adipocyte lipid metabolism and body weight regulation in energy-restricted aP2-agouti transgenic mice.

We have demonstrated previously a regulatory role for intracellular Ca2+ ([Ca2+]i) in adipocyte lipogenesis and lipolysis and have recently reported that 1,25-(OH)2-D increases adipocyte [Ca2+]i, which causes increased lipogenesis and decreased lipolysis. We have now tested the hypothesis that suppressing 1,25-(OH)2-D by increasing dietary calcium will suppress adipocyte [Ca2+]i, thereby facilitating weight loss by stimulating lipolysis and inhibiting lipogenesis in calorically (Kcal)-restricted (70% of ad lib) aP2-agouti transgenic (aP2-a) mice. Mice (aP2-a) exhibiting a pattern of obesity gene expression similar to humans were fed a low-Ca (0.4%)/high-fat/high-sucrose diet for six weeks, resulting in a 27% and twofold increase in body weight and total fat pad mass, respectively, with a twofold increase in adipocyte [Ca2+]i pad lib or Kcal-restricted (70% of ad lib) on this diet either unsupplemented (basal) or with 25% or 50% of the protein replaced by non-fat dry milk (medium or high) dairy or supplemented with CaCO3 to 1.2% Ca for six weeks. Adipocyte [Ca2+]i was unaffected by Kcal restriction but was reduced markedly by all three high Ca diets (290 vs. 130 nM, p2+]i and thereby reduce energy storage and increase thermogenesis during Kcal restriction.

Adipocytes↗

PubMed2000

Transcriptional regulation of the adipocyte fatty acid synthase gene by agouti: interaction with insulin.

Mice carrying dominant mutations at the agouti locus exhibit ectopic expression of agouti gene transcripts, obesity, and type II diabetes through unknown mechanisms. To gain insight into the role of agouti protein in modulating adiposity, we investigated regulation of a key lipogenic gene, fatty acid synthase (FAS) by agouti alone and in combination with insulin. Both agouti and insulin increase FAS activity in 3T3-L1 and in human adipocytes. Agouti and insulin independently and additively increase FAS activity in 3T3-L1 adipocytes. We further investigated the mechanism responsible for the agouti-induced FAS expression in these cells and demonstrated that both insulin (3-fold increase) and agouti (2-fold) increased FAS gene expression at the transcriptional level. Furthermore, insulin and agouti together exerted additive effects (5-fold increase) on FAS gene transcription. Transfection assays of FAS promoter-luciferase fusion gene constructs into 3T3-L1 adipocytes indicated that the agouti response element(s) is (are) located in the -435 to -415 region (-435/-415) of the FAS promoter. Nuclear proteins binding to this novel sequence are adipocyte specific. Thus the agouti response sequences mapped to a region upstream of the insulin-responsive element (which we previously reported to be located at -67/-52), consistent with additive effects of these two factors on FAS gene transcription.

3T3 Cells↗

PubMed2000

Role of intracellular calcium in human adipocyte differentiation.

Intracellular calcium ([Ca(2+)](i)) modulates adipocyte lipid metabolism and inhibits the early stages of murine adipogenesis. Consequently, we evaluated effects of increasing [Ca(2+)](i) in early and late stages of human adipocyte differentiation. Increasing [Ca(2+)](i) with either thapsigargin or A23187 at 0-1 h of differentiation markedly suppressed differentiation, with a 40-70% decrease in triglyceride accumulation and glycerol-3 phosphate dehydrogenase (GPDH) activity (P < 0.005). However, a 1-h pulse of either agent at 47-48 h only modestly inhibited differentiation. Sustained, mild stimulation of Ca(2+) influx with either agouti protein or 10 mM KCl-induced depolarization during 0-48 h of differentiation inhibited triglyceride accumulation and GPDH activity by 20-70% (P < 0.05) and markedly suppressed peroxisome proliferator-activated receptor gamma (PPARgamma) expression. These effects were reversed by Ca(2+) channel antagonism. In contrast, Ca(2+) pulses late in differentiation (71-72 h or 48-72 h) markedly increased these markers of differentiation. Thus increasing [Ca(2+)](i) appears to exert a biphasic regulatory role in human adipocyte differentiation, inhibiting the early stages while promoting the late stage of differentiation and lipid filling.

Adipocytes↗

PubMed2000

Regulation of leptin by agouti.

Dominant mutations at the mouse Agouti locus lead to ectopic expression of the Agouti gene and exhibit diabetes, obesity, and yellow coat color. Obese yellow mice are hyperinsulinemic and hyperleptinemic, and we hypothesized that Agouti directly induces leptin secretion. Accordingly, we used transgenic mice expressing agouti in adipocytes (under the control of aP2 promoter, aP212) to examine changes in leptin levels. Agouti expression in adipose tissue did not significantly alter food intake, weight gain, fat pad weight, or insulinemia; however, the transgenic mice were hyperglycemic. We demonstrated that plasma leptin levels are approximately twofold higher in aP212 transgenic mice compared with their respective controls, whereas ubiquitous expression of agouti (under the control of beta-actin promoter, BAP20) led to a sixfold increase in leptin. Insulin treatment of aP212 mice increased adipocyte leptin content without affecting plasma leptin levels. These findings were further confirmed in vitro in 3T3-L1 adipocytes treated with recombinant Agouti protein and/or insulin. Agouti but not insulin significantly increased leptin secretion, indicating that insulin enhances leptin synthesis but not secretion while Agouti increases both leptin synthesis and secretion. This increased leptin synthesis and secretion was due to increased leptin mRNA levels by Agouti. Interestingly, agouti regulation of leptin was not mediated by melanocortin receptor 4, previously implicated in agouti regulation of food intake. These results suggest that increased leptin secretion by agouti may serve to limit agouti-induced obesity, independent of melanocortin receptor antagonism, and indicate that interaction between obesity genes may play a key role in obesity.

Adipocytes↗

PubMed2000

Relationship between human adipose tissue agouti and fatty acid synthase (FAS).

The human homologue of the murine obesity gene, agouti, is expressed in adipose tissue. We have shown that recombinant agouti protein regulates adipocyte lipogenesis and lipolysis coordinately and promotes lipid storage via a Ca(2+)-dependent mechanism in vitro, which may contribute to agouti-induced obesity. However, little is known about agouti's physiologic function in humans. We first studied the agouti content in human mature adipocytes vs. preadipocytes. The agouti content of human mature adipocytes was five times as abundant as in preadipocytes (19.18 +/- 2.46 vs. 4.07 +/- 0.51 pg/microg protein, P: < 0.005), suggesting that agouti is up-regulated during adipocyte differentiation. We next studied the relationship of agouti mRNA and protein to fatty acid synthase (FAS) mRNA and activity in adipose tissue obtained from nonobese and mildly obese patients (body mass index range, 21-31 kg/m(2)). Agouti protein was correlated with FAS activity (r = 0.782, P: < 0.005). Similarly, human adipose tissue agouti mRNA level was also correlated with FAS mRNA level (r = 0.846, P: < 0.001). These data suggest that agouti may be another adipocyte-produced factor that modulates adipocyte lipid metabolism via a paracrine/autocrine mechanism.

Adipocytes↗

PubMed2000

Pro-opiomelanocortin (POMC) deficiency and peripheral melanocortins in obesity.

Melanocortin peptides, derived from pro-opiomelanocortin (POMC), appear to play a significant role in appetite and body weight regulation. Expression of the Pomc gene in the central nervous system results in the production of melanocortin peptides, which bind to the melanocortin-4 receptor (MC4-R) and inhibit food intake. MC4-R knockout mice exhibit adult-onset obesity, whereas MC4-R agonists suppress food intake in several models of obesity. Recently, Pomc knockout mice were generated and shown to develop hyperphagia and obesity with a time-course and severity comparable to MC4-R knockout mice, whereas daily administration of a stable alpha-melanocyte stimulating hormone analogue reversed this effect. These data clearly implicate POMC peptides and melanocortin receptors in the pathophysiology of obesity and provide important new tools for their development as therapeutic targets in obesity.

Animals↗

PubMed2000

Regulation of adiposity by dietary calcium.

Recent data from this laboratory demonstrate that increasing adipocyte intracellular Ca(2+) results in a coordinated stimulation of lipogenesis and inhibition of lipolysis. We have also noted that increasing dietary calcium of obese patients for 1 year resulted in a 4.9 kg loss of body fat (P<0.01). Accordingly, we tested the possibility that calcitrophic hormones may act on adipocytes to increase Ca(2+) and lipid metabolism by measuring the effects of 1, 25-(OH)(2)-D in primary cultures of human adipocytes, and found significant, sustained increases in intracellular Ca(2+) and a corresponding marked inhibition of lipolysis (EC(50) approximately 50 pM; P<0.001), suggesting that dietary calcium could reduce adipocyte mass by suppressing 1,25-(OH)(2)-D. To test this hypothesis, we placed transgenic mice expressing the agouti gene specifically in adipocytes on a low (0.4%) Ca/high fat/high sucrose diet either unsupplemented or with 25 or 50% of the protein replaced by non-fat dry milk or supplemented to 1.2% Ca with CaCO(3) for 6 wk. Weight gain and fat pad mass were reduced by 26-39% by the three high calcium diets (P<0.001). The high calcium diets exerted a corresponding 51% inhibition of adipocyte fatty acid synthase expression and activity (P<0.002) and stimulation of lipolysis by 3. 4- to 5.2-fold (P<0.015). This concept of calcium modulation of adiposity was further evaluated epidemiologically in the NHANES III data set. After controlling for energy intake, relative risk of being in the highest quartile of body fat was set to 1.00 for the lowest quartile of Ca intake and was reduced to 0.75, 0.40, and 0.16 for the second, third, and fourth quartiles, respectively, of calcium intake for women (n=380;P<0.0009); a similar inverse relationship was also noted in men (n=7114; P<0.0006). Thus, increasing dietary calcium suppresses adipocyte intracellular Ca(2+) and thereby modulates energy metabolism and attenuates obesity risk.

Adipocytes↗

PubMed1999

The agouti gene product stimulates pancreatic [beta]-cell Ca2+ signaling and insulin release.

Ubiquitous expression of the mouse agouti gene results in obesity and hyperinsulinemia. Human agouti is expressed in adipose tissue, and we found recombinant agouti protein to stimulate lipogenesis in adipocytes in a Ca(2+)-dependent fashion. However, adipocyte-specific agouti transgenic mice only became obese in the presence of hyperinsulinemia. Because intracellular Ca(2+) concentration ([Ca(2+)](i)) is a primary signal for insulin release, and we have shown agouti protein to increase [Ca(2+)](i) in several cell types, we examined the effects of agouti on [Ca(2+)](i) and insulin release. We demonstrated the expression of agouti in human pancreas and generated recombinant agouti to study its effects on Ca(2+) signaling and insulin release. Agouti (100 nM) stimulated Ca(2+) influx, [Ca(2+)](i) increase, and a marked stimulation of insulin release in two beta-cell lines (RIN-5F and HIT-T15; P < 0. 05). Agouti exerted comparable effects in isolated human pancreatic islets and beta-cells, with a 5-fold increase in Ca(2+) influx (P < 0.001) and a 2.2-fold increase in insulin release (P < 0.01). These data suggest a potential role for agouti in the development of hyperinsulinemia in humans.

Agouti Signaling Protein↗

PubMed1999

Role of the sulfonylurea receptor in regulating human adipocyte metabolism.

A regulatory role for intracellular Ca2+ ([Ca2+]i) in adipocyte lipogenesis, lipolysis and triglyceride accumulation has been demonstrated. Compounds acting on the pancreatic sulfonylurea receptor (SUR) to increase (e.g., glibenclamide) or decrease (e.g., diazoxide) [Ca2+]i cause corresponding increases and decreases in weight gain. However, these weight gain and loss effects have been attributed to insulin release rather than to the primary effects of these compounds on the adipocyte SUR and its associated K(ATP) channel. Accordingly, we have evaluated the direct role of the human adipocyte SUR in regulating adipocyte metabolism. We used RT-PCR with primers for a highly conserved region of SUR1 to demonstrate that human adipocytes express SUR1. The PCR product was confirmed by sequence analysis and used as a probe to demonstrate adipocyte SUR1 expression by Northern blot analysis. Adipocytes exhibited glibenclamide dose-responsive (0-20 microM) increases in [Ca2+]i (P<0.05). Similarly, glibenclamide (10 microM) caused a 67% increase in adipocyte fatty acid synthase activity (P<0.001), a 48% increase in glycerol-3-phosphate dehydrogenase activity (P<0.01) and a 68% inhibition in lipolysis (P<0.01), whereas diazoxide (10 microM) completely prevented each of these effects. These data demonstrate that human adipocytes express a SUR that regulates [Ca2+]i and, consequently, exerts coordinate control over lipogenesis and lipolysis. Accordingly, the adipocyte SUR1 may represent an important target for the development of therapeutic interventions in obesity.

ATP-Binding Cassette Transporters↗

PubMed1999

Glycemic index, cardiovascular disease, and obesity.

Although Americans have decreased the percent of energy they consume from fat, obesity and obesity-related comorbidities have progressively increased. Less attention has been paid to the role of carbohydrates, especially carbohydrate source, in these metabolic diseases. However, recent epidemiologic studies demonstrate consistently higher rates of cardiovascular disease and type II diabetes in individuals deriving a greater percentage of energy from refined grains and simple carbohydrates than from whole grains. Differences in the metabolic response to carbohydrates can be classified by glycemic index (GI), the blood glucose response to a given food compared with a standard (typically white bread or glucose). Classification of carbohydrates as "simple" or "complex" is of little use in predicting GI, because GI is influenced by starch structure (amylose versus amylopectin), fiber content, food processing, physical structure of the food, and other macronutrients in the meal. Low-GI diets have been reported to lower postprandial glucose and insulin responses, improve lipid profiles, and increase insulin sensitivity. Moreover, high-GI diets stimulate de novo lipogenesis and result in increased adipocyte size, whereas low-GI diets have been reported to inhibit these responses. Thus, the GI of dietary carbohydrates appears to play an important role in the metabolic fate of carbohydrates and, consequently, may significantly affect the risk of cardiovascular disease, diabetes, and obesity.

Blood Glucose↗

PubMed1998

Effects of a potent melanocortin agonist on the diabetic/obese phenotype in yellow mice.

OBJECTIVE: To test the hypothesis that a melanocortin agonist can reverse obesity and insulin resistance in mice overexpressing the agouti protein. EXPERIMENTAL MODEL: Mice overexpressing the agouti protein either by transgene introduction (beta-actin promotor) or by mutation (Ay). DESIGN: NDPMSH was tested for pharmacokinetic suitability. NDPMSH at various doses was administered subcutaneously twice a day for 2-3 weeks. MEASUREMENTS: Fur pigmentation, various fatness parameters (core temperature, fat pad weight and body weight), blood glucose and hormones, fatty acid synthase measurement. RESULTS: NDPMSH caused fur pigmentation and core temperature changes, but failed to affect any metabolic parameters in agouti-dependent manner. CONCLUSION: NDPMSH, as a representation melanocortin agonist, does not compete with agouti in reversing agouti-dependent metabolic effects. This suggests that 1) agouti works via a receptor other than a melanocortin receptor to mediate its metabolic effects, 2) agouti-dependent metabolic effects are mediated through melanocortin receptors but not via antagonism of these receptors, or 3) NDPMSH is pharmacodynamically an inappropriate molecule for these types of studies.

Agouti Signaling Protein↗

PubMed1998

Chromium picolinate modulates rat vascular smooth muscle cell intracellular calcium metabolism.

We have previously shown that insulin attenuates vasoconstriction, accelerates both vascular relaxation and [Ca2+]i recovery from pressor agonist-induced Ca2+ loads, and stimulates Ca2+-ATPase gene expression in rat and human vascular smooth muscle cells (VSMC). Moreover, these functions are impaired in VSMC from both insulin resistant and insulinopenic rats, suggesting that hypertension in insulin resistant states may result, in part, from impaired insulin-regulation of VSMC Ca2+ transport. Accordingly, we have now evaluated the effect of improving cellular insulin sensitivity with chromium picolinate (CrPic) on regulation of VSMC Ca2+ transport. Cultured VSMC from rats were grown from passage to confluence in the presence or absence of 1 micromol/L CrPic, maintained in a quiescent medium for 24 h and incubated with or without insulin (10(-8) mol/L) for the final 2 h. Cells were then harvested and RNA and protein extracted for Northern and Western blot analysis, respectively. Insulin caused a significant stimulation of plasmalemmal Ca2+-ATPase mRNA and protein (P < 0.05). A comparable stimulation of the mRNA and protein levels was caused by CrPic in the absence of insulin (P < 0.05), while the CrPic + insulin treatment caused a greater percentage stimulation of the Ca2+-ATPase mRNA level than either separate treatment (P < 0.05). Fluorometric analysis of the rate of [Ca2+]i recovery following stimulation with arginine vasopressin support these findings: insulin caused an 83% increase, CrPic caused a 35% increase and insulin + CrPic caused a 133% increase in [Ca2+]i recovery rate. These data suggest that CrPic may be an effective modality to reduce VSMC [Ca2+]i loads and thereby reduce peripheral vascular resistance in insulin resistant states.

Animals↗