Michael Zemel

• University of Tennessee at Knoxville

Background Sirtuin 1 (Sirt1) is suppressed in non‐alcoholic fatty liver disease (NAFLD), while its’ stimulation or overexpression results in reduced disease severity in pre‐clinical NAFLD models. Leucine allosterically activates Sirt1 and synergise with other Sirt/AMPK/NO pathway activators. We developed a triple combination of leucine, metformin a...

[This corrects the article on p. 33 in vol. 7, PMID: 28533928.].

Background/aims: Nicotinic acid (NA), a lipid-lowering drug, serves as a source of NAD(+), the cofactor for Sirt1. Leucine (Leu) stimulates the AMPK/Sirt1 axis and amplifies the effects of other AMPK/Sirt1 activating compounds. Therefore, we tested the interactive effects of leucine and low dose NA on AMPK/Sirt1 signaling and downstream effects of...

Background: We have previously shown leucine (Leu) to activate Sirt1 by lowering its KM for NAD(+), thereby amplifying the effects of other sirtuin activators and improving insulin sensitivity. Metformin (Met) converges on this pathway both indirectly (via AMPK) and by direct activation of Sirt1, and we recently found Leu to synergize with Met to...

Sirt1, AMPK, and eNOS modulate hepatic energy metabolism and inflammation and are key players in the development of NASH. L-leucine, an allosteric Sirt1 activator, synergizes with low doses of metformin or sildenafil on the AMPK-eNOS-Sirt1 pathway to reverse mild NAFLD in preclinical mouse models. Here we tested a possible multicomponent synergy to...

The beneficial effects of leucine and resveratrol on health are largely dependent on activation of the sirtuin pathway. The silent information regulator (Sir) proteins, also called sirtuins, are a conserved family of histone and protein deacetylases that use NAD+ as a co-substrate [1]. This NAD+-dependence links sirtuins to the metabolic activity o...

Purpose Leucine activates SIRT1/AMP-activated protein kinase (AMPK) signaling and markedly potentiates the effects of other sirtuin and AMPK activators on insulin signaling and lipid metabolism. Phosphodiesterase 5 inhibition increases nitric oxide–cGMP signaling, which in turn exhibits a positive feedback loop with both SIRT1 and AMPK, thus amplif...

Lactobacillus rhamnosus GG, Lactobacillus paracasei TMC0409, Streptococcus thermophilus TMC1543 and whey proteins were used to prepare fermented milk. For the experiment aP2- agouti transgenic mice were pre-treated with a high-sucrose/high-fat diet for 6 weeks to induce obesity. The obese mice were fed a diet containing 1·2 % Ca and either non-fat...

Previous studies from this laboratory demonstrate that dietary leucine protects against high fat diet-induced mitochondrial impairments and stimulates mitochondrial biogenesis and energy partitioning from adipocytes to muscle cells through SIRT1-mediated mechanisms. Moreover, β-hydroxy-β-methyl butyrate (HMB), a metabolite of leucine, has been repo...

Leucine activates Sirt1 signaling and markedly potentiates the effects of other activators on sirtuin signaling and downstream effects, including insulin signaling. PDE5 inhibition increases NO‐cGMP signaling, converging with sirtuins on PGC‐1 and mitochondrial biogenesis and thereby modulating insulin sensitivity. We confirmed this synergy in vitr...

The AMPK-Sirt1 pathway is an important regulator of energy metabolism and therefore a potential target for prevention and therapy of metabolic diseases. We recently demonstrated leucine and its metabolite β-hydroxy-β-methylbutyrate (HMB) to synergize with low-dose resveratrol (200 nM) to activate sirtuin signaling and stimulate energy metabolism. H...

Compositions and methods useful for inducing an increase in fatty acid oxidation or mitochondrial biogenesis, reducing weight gain, inducing weight loss, or increasing Sirt1, Sirt3, or AMPK activity are provided herein. Such compositions can contain synergizing amounts of a sirtuin-pathway activators, including but not limited to resveratrol, in co...

Background We recently demonstrated leucine to modulate energy partitioning between adipose tissue and muscle. Further, leucine exhibits a synergy with B6, resulting in reduced adipocyte lipid storage coupled with increased muscle fat oxidation. Accordingly, a nutraceutical (NuShape™) containing 2.25 g leucine and 30 mg B6 increased fat oxidation b...

Effects of leucine-B6 combination on AMPK, PGC-1α, mitochondrial mass, and fatty acid oxidation. Differentiated adipocytes and C2C12 muscle cells were treated with the treatments indicated for 24 hours. (A) Phospho (Thr 172)-AMPK and (B) PGC-1α protein expression was detected by Western blot and quantitatively analyzed. (C) Mitochondrial mass was m...

Background The purpose of this study was to determine whether a mixture of the polyphenol, resveratrol, and the leucine metabolite, hydroxymethylbutyrate (HMB), acts synergistically with low doses of metformin to impact insulin sensitivity and AMP-activated protein kinase-dependent outcomes in cell culture and in diabetic mice. Methods C2C12 skele...

Background: The purpose of this study was to determine whether a mixture of the polyphenol, resveratrol, and the leucine metabolite, hydroxymethylbutyrate (HMB), acts synergistically with low doses of metformin to impact insulin sensitivity and AMP-activated protein kinase-dependent outcomes in cell culture and in diabetic mice. Methods: C2C12 skel...

Background Sirtuins are important regulators of glucose and fat metabolism, and sirtuin activation has been proposed as a therapeutic target for insulin resistance and diabetes. We have shown leucine to increase mitochondrial biogenesis and fat oxidation via Sirt1 dependent pathways. Resveratrol is a widely recognized activator of Sirt; however, th...

Leucine stimulates tissue protein synthesis and may also attenuate adiposity by increasing fatty acid oxidation and mitochondrial biogenesis in muscle and adipocytes. Accordingly, the effects of a nutraceutical containing 2.25 g leucine and 30 mg pyridoxine (Vitamin B6) (NuFit active blend) were tested in cell culture and in a clinical trial. 3T3L1...

Recent data from this laboratory suggest that components of dairy foods may serve as activators of SIRT1 (Silent Information Regulator Transcript 1), and thereby participate in regulation of glucose and lipid metabolism. In this study, an ex-vivo/in-vitro approach was used to examine the integrated effects of dairy diets on SIRT1 activation in two...

ABSTRACT: Insufficient calcium intake has been proposed to cause unbalanced energy partitioning leading to obesity. However, weight loss interventions including dietary calcium or dairy product consumption have not reported changes in lipid metabolism measured by the plasma lipidome. The objective of this study was to determine the relationships be...

Oxidative and inflammatory stress are elevated in obesity and are further augmented in metabolic syndrome. We showed previously that dairy components suppress the adipocyte- and macrophage-mediated generation of reactive oxygen species and inflammatory cytokines and systemic oxidative and inflammatory biomarkers in obesity. The objective of this st...

Weight loss is achieved through the consumption of a hypoenergetic diet and/or increased energy expenditure through exercise. While weight loss is associated with numerous benefits, the pattern of weight loss in terms of body composition changes is not always studied. In our view, the optimum pattern of weight loss is one in which fat mass is lost...

Calcitriol has recently been demonstrated to play an important role in modulating adipocyte function by regulating adipocyte lipid metabolism and energy homeostasis via both genomic and non-genomic actions. Physiological concentrations of calcitriol dose-dependently inhibit adipocyte apoptosis, although supra-physiological concentrations stimulate...

We recently showed that calcitriol increases oxidative and inflammatory stress; moreover, inhibition of calcitriol with high-calcium diets decreased both adipose tissue and systemic oxidative and inflammatory stress in obese mice, whereas dairy exerted a greater effect. However, these findings may be confounded by concomitant changes in adiposity....

To determine the long-term effect of a randomized controlled trial of a dairy-rich diet on generalized and abdominal obesity, as well as on the components of the metabolic syndrome, among obese prepubescent children. This trial was conducted among a population-based sample of 120 obese prepubescent children who were randomly assigned to 3 groups of...

Oxidative and inflammatory stress have been implicated as major contributors to the aging process. Dietary Ca reduced both factors in short-term interventions, while milk exerted a greater effect than supplemental Ca. In this work, we examined the effects of life-long supplemental and dairy calcium on lifespan and life-span related biomarkers in aP...

A 12-week randomized controlled multi-center clinical trial was conducted in 106 overweight and obese adults. Diets were designed to produce a 2,093 kJ/day energy deficit with either low calcium (LC; ~600 mg/day), high calcium (HC; ~1,400 mg/day), or high dairy (HD; three dairy servings, diet totaling ~1,400 mg/day). Ninety-three subjects completed...

The effects of dairy on energy metabolism appear to be mediated, in part, by leucine and calcium which regulate both adipocyte and skeletal muscle energy metabolism. We recently demonstrated that leucine and calcitriol regulate fatty acid oxidation in skeletal muscle cells in vitro, with leucine promoting and calcitriol suppressing fatty acid oxida...

Dietary calcium and dairy foods have demonstrated an antiobesity effect in animal studies, observational and population studies, and randomized clinical trials. Moreover, there is a strong theoretical framework to explain the effects of dietary calcium on energy metabolism. The supporting mechanisms include dietary calcium-correcting suboptimal cal...

Consumption of dairy foods has been associated with lower blood pressure in certain populations. This study examined the effects of dairy foods on blood pressure (BP) and intracellular calcium ((Ca)(i)) and the dependence of BP changes on changes in (Ca)(i). Twenty-three stage 1 hypertensive adults were fed the following 3 experimental diets (5 wk...

Dietary weight loss regimens could be more effective by selectively targeting adipose while sparing lean mass (LM) if predictive information about individuals' lipid metabolic responses to an intervention were available. The objective of this study was to examine the relationships among changes in 4 anthropometric outcomes, weight, waist circumfere...

An anti-obesity effect of dietary calcium and dairy foods is evident from animal studies, observational and population studies, and randomized clinical trials. Dietary calcium appears to be responsible for 50% of the anti-obesity bioactivity of dairy. The additional dairy bioactivity has not been fully identified, but is localized primarily in whey...

High-calcium diets modulate energy metabolism and suppress inflammatory stress. These effects are primarily mediated by calcium suppression of calcitriol. We have now investigated the effect of additional components in dairy products [branched-chain amino acids (BCAA) and angiotensin-converting enzyme inhibitors (ACEi)] on adipocyte and muscle meta...

In their recent assessment of clinical trials evaluating the hypothesis that dairy foods favorably impact weight management, Lanou and Barnard1 have overlooked several key facts. First, the dairy and weight management hypothesis does not predict an effect of dairy on body weight loss in the absence of energy restriction. Instead, it predicts an aug...

To compare the effects of low versus recommended levels of dairy intake on weight maintenance and body composition subsequent to weight loss. Design and Methods Two site (University of Kansas-KU; University of Tennessee-UT), 9 month, randomized trial. Weight loss was baseline to 3 months, weight maintenance was 4 to 9 months. Participants were main...

Calcitriol, a calcitrophic hormone that can be suppressed by high dietary calcium, favors fatty acid synthesis and inhibits lipolysis via non-genomic modulation of Ca(2+) influx. Calcitriol also suppresses UCP2 expression via the nVDR and thereby increases energy efficiency. Calcitriol exerts a dose-dependent impact on adipocyte apoptosis and regul...

The purpose of this study was to investigate the impact of dietary calcium or dairy product intake on total energy expenditure (TEE), fat oxidation, and thermic effect of a meal (TEM) during a weight loss trial. The intervention included a prescribed 500-kcal deficit diet in a randomized placebo-controlled calcium or dairy product intervention empl...

Objective: The objective of this study was to investigate the effects of calcitriol on adipocyte and macrophage cytokine expression as well as release and on adipocyte-macrophage cross-talk in local modulation of inflammation. Research procedures and results: We investigated calcitriol modulation of the expression of macrophage inhibitory factor...

Dietary calcium plays a key role in the regulation of energy metabolism and obesity risk. This appears to be mediated primarily by dietary calcium modulation of circulating calcitriol, which in turn regulates adipocyte intracellular calcium ([Ca2+]i). Increased [Ca2]i stimulates lipogenic gene expression and activity and inhibits lipolysis, resulti...

We have recently shown 1alpha,25-dihydroxycholecalciferol increased oxidative stress and inflammatory stress in vitro, whereas suppression of 1alpha,25-dihydroxycholecalciferol with dietary calcium (Ca) decreased oxidative and inflammatory stress in vivo. However, dairy products contains additional factors, such as angiotensin-converting enzyme inh...

We previously demonstrated that high calcium diets inhibit obesity in both mice and humans; this effect is mediated, in part, by dietary calcium suppression of 1alpha, 25-dihydroxyvitamin D, which exerts both non-genomic and genomic effects on adipocyte metabolism. However, the presence of the nuclear vitamin D receptor (nVDR) and its role in this...

The influence of calcium and dairy food intake on energy balance is the object of a growing scientific literature. This manuscript presents the information discussed by subject experts during a symposium on calcium and obesity, initially planned to document in a comprehensive manner the role of calcium and dairy food on energy balance and body comp...

Dietary calcium inhibits adiposity, and a key underlying mechanism is suppression of calcitriol, which modulates Ca(2+) signaling and mitochondrial uncoupling in adipocytes. We demonstrated that calcitriol directly regulates adipocyte 11beta-HSD-1 expression and cortisol production in human adipocytes in vitro and dietary calcium inhibits visceral...

We have previously shown 1alpha,25-dihydroxyvitamin D3 [1alpha,25-(OH)2D3] to inhibit mitochondrial uncoupling protein 2 (UCP2) expression in adipocytes and that in vivo suppression of calcitriol levels with calcium-rich diets increases UCP2 expression. Because UCP2 plays a significant role in the clearance of reactive oxygen species (ROS), we stud...

Fresh soymilk was prepared with 9:1 and 7:1, water:dry soybeans ratio, and fermented with commercial freeze-dried starter cultures comprising three lactics, L. acidophilus. S. thermophilus, and L. bulgaricus. pH and titratable acidity reached their lowest and highest values, respectively, after 8 h of incubation at 43° C. Addition of sucrose did no...

Dietary calcium modulation of adiposity is mediated, in part, by suppression of calcitriol, while the additional effect of dairy products is mediated by additional components; these include the high concentration of leucine, a key factor in the regulation of muscle protein turnover. We investigated the effect of leucine, calcitriol and calcium on e...

Obesity is associated with elevated oxidative stress and low-grade systemic inflammation. We have demonstrated recently that 1alpha,25-(OH)(2)-D(3) promotes reactive oxygen species production in cultured adipocytes, whereas suppression of 1alpha,25-(OH)(2)-D(3) by increasing dietary calcium down-regulates diet-induced oxidative stress in aP2-agouti...

Although high-calcium diets have been reported to reduce the risk of colorectal cancer, our preliminary data with the adenomatous polyposis coli (Apc) Min mutation (Min/+;Apc(Min/+)) mouse shows a paradoxical increase in intestinal tumor loads (> 65%) with high calcium diets. Since we previously demonstrated that increasing dietary calcium reduces...

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. We fed low-calcium (0.4% Ca) and high-calcium (1.2% Ca from CaCO3) obesity-promoting (high sucrose...

The effects of nonfat dry milk, CaCO3, CaCl2 and MgCl2 on phytate hydrolysis and on Zn and Fe availability was evaluated in whole wheat bread and in a model fermentation system. CaCO3 and CaCl2 both depressed phytate hydrolysis to an equivalent degree, but the milk had a greater effect than could be accounted for by its Ca content. MgCl2 had a less...

Effects of orthophosphate, tripolyphosphate and hexametaphosphate on zinc, iron and calcium availability were evaluated following in vitro peptic and peptic-pancreatic digestions. Solubility was used as an index of potential availability for zinc and calcium; both total soluble and ionized levels were considered for iron. Orthophos-phate depressed...

Calcium solubility from sea mustard was compared to that of spinach and milk in an in vitro digestive system with normal and reduced gastric acid concentrations. Aliquots of each were subjected to peptic and pancreatic digestions, and ionic and total soluble calcium levels were measured as indices of potential availability. Solubility of calcium fr...

Male weanling tats were fed an adequate diet supplemented with 0.42% P from either hexametaphosphate or orthophosphate, each at two levels of Ca intake (0.53% or 1.06%). Polyphosphates represented 13% of the total fecal phosphorus at the 0.53% Ca intake; this fraction was increased to 27% at the 1.06% Ca intake. Hexametaphosphate caused a 15% incre...

The effects of three levels (0.1, 0.3 and 0.5%) of locust bean gum, guar gum and sodium alginate on zinc and iron availability were evaluated in milk and soy systems. Availability was estimated as metal solubility after digestion with pepsin-HCl followed by addition of bicarbonate and digestion with pancreatic and bile extracts. Locust bean gum (0....

Higher calcium and dairy intakes may be associated with lower body weights, but a mechanism in humans has yet to be elucidated. We compared the effects of a dairy-based high-calcium diet and a low-calcium diet on macronutrient oxidation. Subjects (10 men and nine women) consumed a low-dairy (LD, approximately one serving per day, approximately 500...

Dietary calcium appears to play a pivotal role in the regulation of energy metabolism and obesity risk. High calcium diets attenuate body fat accumulation and weight gain during periods of over-consumption of an energy-dense diet and to increase fat breakdown and preserve metabolism during caloric restriction, thereby markedly accelerating weight a...

Studies suggest that high-dairy and high-fiber/low-glycemic index diets may facilitate weight loss, but data are conflicting. The effects on weight loss and body fat of a high-dairy diet and a diet high in dairy and fiber and low in glycemic index were compared with a standard diet. Ninety obese subjects were recruited into a randomized trial of th...

Our objective was to determine the effects of dairy consumption on adiposity and body composition in obese African Americans. We performed two randomized trials in obese African-American adults. In the first (weight maintenance), 34 subjects were maintained on a low calcium (500 mg/d)/low dairy (<1 serving/d) or high dairy (1200 mg Ca/d diet includ...

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. Obese...

1,25-Dihydroxyvitamin D3 dose dependently increases intracellular calcium in human adipocytes. We have demonstrated that suppression of circulating 1,25-dihydroxyvitamin D3 levels by increasing dietary calcium reduces adipocyte intracellular calcium and reduces adiposity in both humans and rodents, with preferential loss of trunk fat. Autocrine pro...

Our objective was to evaluate the effects of a qualitative change in dietary carbohydrate source on body weight and adiposity in a rodent model of diet-induced obesity. We evaluated the effects of high-fat diets (basal) varying in carbohydrate source in aP2-agouti transgenic mice. In the ad libitum study, animals were given free access to the basal...

We demonstrated previously that dietary calcium suppression of calcitriol reduces adipocyte Ca(2+), suppresses lipogenesis, and increases lipid utilization during energy restriction. Notably, dairy calcium sources exert markedly greater effects. To determine the effects of dietary calcium and dairy products on energy partitioning during subsequent...

We previously found that 1alpha, 25-dihydroxyvitamin D3 [1alpha, 25-(OH)2-D3] modulates adipocyte lipid metabolism via a Ca2+-dependent mechanism and inhibits adipocyte UCP2 expression, indicating that the anti-obesity effects of dietary calcium are mediated by suppression of 1alpha, 25-(OH)2-D3 levels. However, because UCP2 reduces mitochondrial p...

Dietary calcium plays a pivotal role in the regulation of energy metabolism because high-calcium diets attenuate adipocyte lipid accretion and weight gain during the overconsumption of an energy-dense diet and increase lipolysis and preserve thermogenesis during caloric restriction, which thereby markedly accelerates weight loss. Intracellular Ca(2...

Dietary calcium plays a key role in the regulation of energy metabolism and obesity risk. This appears to be mediated primarily by dietary calcium modulation of circulating calcitriol, which in turn regulates adipocyte intracellular calcium ([Ca2+]i). Increased [Ca2+]i stimulates lipogenic gene expression and activity and inhibits lipolysis, result...

Increasing 1,25-dihydroxyvitamin D in response to low-calcium diets stimulates adipocyte Ca2+ influx and, as a consequence, stimulates lipogenesis, suppresses lipolysis, and increases lipid accumulation, whereas increasing dietary calcium inhibits these effects and markedly accelerates fat loss in mice subjected to caloric restriction. Our objectiv...

Whey proteins and amino acid supplements have a strong position in the sports nutrition market based on the purported quality of proteins and amino acids they provide. Recent studies employing stable isotope methodology demonstrate the ability of whey proteins or amino acid mixtures of similar composition to promote whole body and muscle protein sy...

Previous data from this laboratory demonstrate that increased intracellular Ca(2+) ([Ca(2+)]i) coordinately regulates human and murine adipocyte lipid metabolism by stimulating lipogenesis and inhibiting lipolysis. However, recent data demonstrate metabolic uncoupling increases [Ca(2+)]i but inhibits lipogenesis by suppressing fatty acid synthase (...

Individuals exhibiting "the metabolic syndrome" have multiple coronary artery disease risk factors, including insulin resistance, hyperlipidemia, hypertension, and android obesity. We performed a randomized trial to compare the effects of aerobic and resistance training regimens on coronary risk factors. Twenty-six volunteers who exhibited android...

Dietary calcium plays a pivotal role in the regulation of energy metabolism. High-calcium diets attenuate adipocyte lipid accretion and weight gain during overconsumption of an energy-dense diet and increase lipolysis and preserve thermogenesis during caloric restriction, thereby markedly accelerating weight loss. Our studies of the agouti gene dem...

Dietary calcium plays a pivotal role in the regulation of energy metabolism, in that we have found high calcium diets to attenuate adipocyte lipid accretion and weight gain during periods of overconsumption of an energy-dense diet and to increase lipolysis and preserve thermogenesis during caloric restriction, thereby markedly accelerating weight l...

Rats carrying one copy of the fa allele are predisposed to diet-induced metabolic disturbances which contribute to hyperinsulinemia, obesity and dyslipidemia. To investigate the role of dietary carbohydrate and fat in the development of these conditions, we fed 6-week old male heterozygous (fa/+) lean rats carbohydrate-free diets containing primari...

We recently demonstrated that suppressing 1alpha,25-(OH)2-D3 by increasing dietary calcium decreases adipocyte intracellular Ca2+ ([Ca2+]i), stimulates lipolysis, and inhibits lipogenesis. High calcium diets also increase core temperature and white adipose tissue uncoupling protein 2 (UCP2) expression in aP2-agouti transgenic mice. Accordingly, we...

Leptin is an adipocyte-secreted hormone that binds hypothalamic receptors and potently decreases food intake. Leptin receptor defects in homozygous mutant Zucker fatty ( fa/fa) rats lead to massive obesity, hyperphagia, decreased energy expenditure, and insulin resistance, while the phenotype of heterozygous ( Fa/fa) lean rats lies between lean ( F...

Dietary calcium plays a pivotal role in the regulation of energy metabolism; high calcium diets attenuate adipocyte lipid accretion and weight gain during periods of overconsumption of an energy-dense diet and increase lipolysis and preserve thermogenesis during caloric restriction, thereby markedly accelerating weight loss. Intracellular Ca2+ has...

Nonsteroidal anti-inflammatory drugs (NSAIDs) are antitumorigenic in humans as well as in animal models of intestinal neoplasia, such as the adenomatous polyposis coli (Min/+) (Apc(Min/+)) mouse. NSAIDs inhibit cyclooxygenase (COX) isozymes, which are responsible for the committed step in prostaglandin biosynthesis, and this has been considered the...

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 an...

We reported recently that suppression of the renal 1 alpha ,25-dihyroxyvitamin D-3 (1 alpha ,25-(OH)(2)-D-3) production in aP2-agouti transgenic mice by increasing dietary calcium decreases adiposity. However, it was not clear whether this modulation of adipocyte metabolism by dietary calcium is a direct effect of inhibition of 1 alpha ,25-(OH)(2)-...

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....

Ectopic overexpression of the murine agouti gene results in yellow coat color, obesity, hyperinsulinemia, and type II diabe- tes. We have shown the human homologue of agouti (agouti signaling protein; ASP) to regulate human adipocyte metabo- lism and lipid storage via a Ca2+-dependent mechanism. We have also demonstrated agouti expression in human...

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...

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 combinatio...

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...

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 suppre...

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 exhibi...

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 calci...

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 th...

We have previously reported that attenuation of hyperinsulinemia by diazoxide (DZ), an inhibitor of glucose-mediated insulin secretion, increased insulin sensitivity and reduced body weight in obese Zucker rats. These findings prompted us to investigate the effects of DZ on key insulin-sensitive enzymes regulating adipose tissue metabolism, fatty a...