An enhanced metabolic efficiency for accelerating the recovery of fat mass (or catch-up fat) is a... more An enhanced metabolic efficiency for accelerating the recovery of fat mass (or catch-up fat) is a characteristic feature of body weight regulation after weight loss or growth retardation and is the outcome of an "adipose-specific" suppression of thermogenesis, i.e., a feedback control system in which signals from the depleted adipose tissue fat stores exert a suppressive effect on thermogenesis. Using a previously described rat model of semistarvation-refeeding in which catch-up fat results from suppressed thermogenesis per se, we report here that the gene expression of stearoyl-coenzyme A desaturase 1 (SCD1) is elevated in skeletal muscle after 2 wk of semistarvation and remains elevated in parallel to the phase of suppressed thermogenesis favoring catch-up fat during refeeding. These elevations in the SCD1 transcript are skeletal muscle specific and are associated with elevations in microsomal ⌬9 desaturase enzyme activity, in the ⌬9 desaturation index, and in the relative content of SCD1-derived monounsaturates in several lipid fractions extracted from skeletal muscle. An elevated skeletal muscle SCD1, by desaturating the products of de novo lipogenesis and diverting them away from mitochondrial oxidation, would inhibit substrate cycling between de novo lipogenesis and lipid oxidation, thereby leading to a state of suppressed thermogenesis that regulates the body's fat storesA role for skeletal muscle stearoyl-CoA desaturase 1 in control of thermogenesis. FASEB J. 20, E1157-E1170 (2006)
Brown adipose tissue (BAT) has been recognized for more than 20 years to play a key role in cold-... more Brown adipose tissue (BAT) has been recognized for more than 20 years to play a key role in cold-induced non-shivering thermogenesis (CIT, NST), and body weight homeostasis in animals. BAT is a flexible tissue that can be recruited by stimuli (including small molecules in animals), and atrophies in the absence of a stimulus. In fact, the contribution of BAT (and UCP1) to resting metabolic rate and healthy body weight homeostasis in animals (rodents) is now well established. Many investigations have shown that resistance to obesity and associated disorders in various rodent models is due to increased BAT mass and the number of brown adipocytes or UCP1 expression in various depots. The recent discovery of active BAT in adult humans has rekindled the notion that BAT is a therapeutic target for combating obesity-related metabolic disorders. In this review, we highlight investigations performed in rodents that support the contention that activation of BAT formation and/or function in obe...
Mice lacking beta-adrenoceptors, which mediate the thermogenic effects of norepinephrine and epin... more Mice lacking beta-adrenoceptors, which mediate the thermogenic effects of norepinephrine and epinephrine, show diminished thermogenesis and high susceptibility to obesity, whereas mice lacking stearoyl-CoA desaturase 1 (SCD1), which catalyzes the synthesis of monounsaturated fatty acids, show enhanced thermogenesis and high resistance to obesity. In testing whether beta-adrenergic control of thermogenesis might be mediated via repression of the SCD1 gene, we found that in mice lacking beta-adrenoceptors, the gene expression of SCD1 is elevated in liver, skeletal muscle and white adipose tissue. In none of these tissues/organs, however, could a link be found between increased sympathetic nervous system activity and diminished SCD1 gene expression when thermogenesis is increased in response to diet or cold, nor is the SCD1 transcript repressed by the administration of epinephrine. Taken together, these studies suggest that the elevated SCD1 transcript in tissues of mice lacking beta-a...
A new member of the uncoupling protein (UCP) family called UCP3 has recently been cloned and show... more A new member of the uncoupling protein (UCP) family called UCP3 has recently been cloned and shown to be highly expressed in skeletal muscle of rodents and humans. In the present study, UCP3 was overexpressed in C 2 C 12 myoblasts where it acts as an uncoupling protein.
The prevalence of Type 2 diabetes is increasing at an alarming rate in most parts of the world. E... more The prevalence of Type 2 diabetes is increasing at an alarming rate in most parts of the world. Effective therapeutic drugs are urgently needed, not only to control the disease but also to prevent or delay its progression. Therapies that target the underlying pathogenesis could, in theory, hold such potential. Recent evidence strongly suggests that impaired mitochondrial function is part of the underlying pathogenesis of insulin resistance and Type 2 diabetes. Peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC-1alpha) is a transcription co-activator that plays a key role in regulating mitochondrial biogenesis and energy metabolism in multiple tissues. Thus, improvement and restoration of mitochondrial function and oxidative capacity through activation of PGC-1alpha could provide new treatments for metabolic diseases. A diverse array of proteins has been shown to regulate PGC-1alpha transcription and/or activity, some of which represent promising targets for pharmaceutical intervention.
Annual Review of Pharmacology and Toxicology, 2007
The unabated rise in the prevalence of obesity is a challenge for global health care systems. Eff... more The unabated rise in the prevalence of obesity is a challenge for global health care systems. Efforts to reverse this trend by dietary or behavioral counseling have not been successful, which has stimulated efforts to find a role for pharmacotherapy. Currently only a small number of antiobesity drugs are approved for long-term use and only a few compounds are in clinical development. Despite recent progress in the understanding of the regulation of energy balance, drug discovery has been less productive than expected. In the present review, the clinically available antiobesity agents are discussed. Examples of drug candidates that are currently in development are given and the possible future range of antiobesity agents is illustrated by the targets being addressed in drug discovery. Finally, the efficacy of antiobesity agents and their value in the treatment of obesity are assessed in comparison with other therapeutic approaches, such as surgery and changes in lifestyle.
Calorie restriction extends lifespan and produces a metabolic profile desirable for treating dise... more Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes 1,2 . SIRT1, an NAD + -dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity 3-9 . Resveratrol, a polyphenolic SIRT1 activator, mimics the antiageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival 10-14 . Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.
This is a measure of limited dietary energy intake in which the physiological effects are seen in... more This is a measure of limited dietary energy intake in which the physiological effects are seen in the form of improved health and ageing by delaying the onset of age-associated diseases. A common diet-restriction regimen used in experimental animals is a 30% reduction in food intake.
The RR-enantiomer of the beta 3-adrenergic receptor agonist BRL 37344 was tritiated to yield a hi... more The RR-enantiomer of the beta 3-adrenergic receptor agonist BRL 37344 was tritiated to yield a high specific activity compound, [3H]SB 206606. This new, potentially specific, beta 3-adrenergic receptor ligand was characterized by binding studies using membranes from both Chinese hamster ovary K1 cells transfected with the rat beta 3-adrenergic receptor and rat interscapular brown adipose tissue, where beta 1-, beta 2-, and beta 3-adrenergic receptor subtypes are known to coexist. [3H]SB 206606 was found to bind to a single population of binding sites in both preparations. The Kd values for [3H]SB 206606 binding to membranes from Chinese hamster ovary K1 cells and brown adipose tissue were quite comparable (58 and 38 nM, respectively). At 37 degrees, the time courses of association and dissociation of [3H]SB 206606 with membranes of brown adipose tissue were quite short. At 4 degrees, the T1/2 were found to be 13 and 40 min, respectively. The Ki values for various beta-adrenergic ago...
The earliest defect in developing type 2 diabetes is insulin resistance, characterized by decreas... more The earliest defect in developing type 2 diabetes is insulin resistance, characterized by decreased glucose transport and metabolism in muscle and adipocytes. The glucose transporter GLUT4 mediates insulin-stimulated glucose uptake in adipocytes and muscle by rapidly moving from intracellular storage sites to the plasma membrane. In insulin-resistant states such as obesity and type 2 diabetes, GLUT4 expression is decreased in adipose tissue but preserved in muscle. Because skeletal muscle is the main site of insulin-stimulated glucose uptake, the role of adipose tissue GLUT4 downregulation in the pathogenesis of insulin resistance and diabetes is unclear. To determine the role of adipose GLUT4 in glucose homeostasis, we used Cre/loxP DNA recombination to generate mice with adipose-selective reduction of GLUT4 (G4A-/-). Here we show that these mice have normal growth and adipose mass despite markedly impaired insulin-stimulated glucose uptake in adipocytes. Although GLUT4 expression ...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 1998
Endurance exercise training has been shown to decrease diet-induced thermogenesis (DIT) in rats a... more Endurance exercise training has been shown to decrease diet-induced thermogenesis (DIT) in rats and humans. In rodents, most thermogenesis is thought to occur in brown adipose tissue via activation of the uncoupling protein-1 (UCP1) and in skeletal muscle. Since the level of UCP1 mRNA in rat BAT was reported to be unmodified by exercise training, the newly described uncoupling proteins UCP2 and UCP3 could be responsible for the decreased DIT in trained rats. UCP3 mRNA levels in endurance-trained rats were found to be reduced by 76% and 59% in tibialis anterior and soleus muscles, respectively. UCP2 mRNA levels were also decreased in tibialis anterior and in heart by 54% and 41%, respectively. Neither white adipose tissue UCP2 nor brown adipose tissue UCP1, UCP2, and UCP3 mRNA levels were modified. The results of this study show that a need for a higher metabolic efficiency is associated with decreased mRNA expression of the uncoupling proteins in skeletal and heart muscles, which wo...
Glucose homeostasis was investigated in ad libitum fed, young and adult male wild-type, loxTB Mc4... more Glucose homeostasis was investigated in ad libitum fed, young and adult male wild-type, loxTB Mc4r and Sim1-Cre, loxTB Mc4r mice. At 5 weeks of age, loxTB Mc4r mice were significantly hyperglycemic and hyperinsulinemic ( ). Sim1-Cre, loxTB Mc4r mice also had elevated serum glucose and insulin levels, albeit levels were not as high as observed in loxTB Mc4r mice. At 12 weeks of age, loxTB Mc4r mice developed severe hyperinsulinemia with increased glucose levels. Sim1-Cre, loxTB Mc4r mice, however, were normoglycemic, but still had significantly elevated insulin levels ( ). These data indicate that PVH and/or amygdala Mc4r re-expression can ameliorate the profound loxTB Mc4r diabetes, but that MC4Rs in other areas may contribute to the regulation of melanocortin-mediated regulation of glucose homeostasis. However, given the altered body composition of Sim1-Cre, loxTB Mc4r mice compared with wild-type mice and loxTB Mc4r mice, and the known effects of increased fat stores on type 2 diabetes, caution must be used when interpreting the insulin/glucose homeostasis data.
0 ]. cDNAs were further amplified using the following primers: [5 0 -CGC TCG AGT GCA GAA TTC-3 0 ... more 0 ]. cDNAs were further amplified using the following primers: [5 0 -CGC TCG AGT GCA GAA TTC-3 0 ] and [5 0 -GCC GCT CGA GTG CAG AT TCN NNN NCG AGA-3 0 ]. Primers were designed based on ref. 13, with modification to minimize the likelihood of inadvertently favouring the amplification of any specific known plant DNA sequence(s). The resulting cDNAs were further amplified by PCR using primers: 5 0 -AAC AGG GTA CGG TGG AAG TG-3 0 and 5 0 -ATC CTC CAG TAC CAG GAA GC-3 0 , which correspond to nucleotide positions 395 to 675 of dehydrin DHN1 (GenBank accession no. X63061) 12 . The resultant PCR product was cloned into TOPO TA cloning vector (Invitrogen) and sequenced.
An enhanced metabolic efficiency for accelerating the recovery of fat mass (or catch-up fat) is a... more An enhanced metabolic efficiency for accelerating the recovery of fat mass (or catch-up fat) is a characteristic feature of body weight regulation after weight loss or growth retardation and is the outcome of an "adipose-specific" suppression of thermogenesis, i.e., a feedback control system in which signals from the depleted adipose tissue fat stores exert a suppressive effect on thermogenesis. Using a previously described rat model of semistarvation-refeeding in which catch-up fat results from suppressed thermogenesis per se, we report here that the gene expression of stearoyl-coenzyme A desaturase 1 (SCD1) is elevated in skeletal muscle after 2 wk of semistarvation and remains elevated in parallel to the phase of suppressed thermogenesis favoring catch-up fat during refeeding. These elevations in the SCD1 transcript are skeletal muscle specific and are associated with elevations in microsomal ⌬9 desaturase enzyme activity, in the ⌬9 desaturation index, and in the relative content of SCD1-derived monounsaturates in several lipid fractions extracted from skeletal muscle. An elevated skeletal muscle SCD1, by desaturating the products of de novo lipogenesis and diverting them away from mitochondrial oxidation, would inhibit substrate cycling between de novo lipogenesis and lipid oxidation, thereby leading to a state of suppressed thermogenesis that regulates the body's fat storesA role for skeletal muscle stearoyl-CoA desaturase 1 in control of thermogenesis. FASEB J. 20, E1157-E1170 (2006)
The neural pathways through which central serotonergic systems regulate food intake and body weig... more The neural pathways through which central serotonergic systems regulate food intake and body weight remain to be fully elucidated. We report that serotonin, via action at serotonin1B receptors (5-HT 1B Rs), modulates the endogenous release of both agonists and antagonists of the melanocortin receptors, which are a core component of the central circuitry controlling body weight homeostasis. We also show that serotonin-induced hypophagia requires downstream activation of melanocortin 4, but not melanocortin 3, receptors. These results identify a primary mechanism underlying the serotonergic regulation of energy balance and provide an example of a centrally derived signal that reciprocally regulates melanocortin receptor agonists and antagonists in a similar manner to peripheral adiposity signals.
This is a measure of limited dietary energy intake in which the physiological effects are seen in... more This is a measure of limited dietary energy intake in which the physiological effects are seen in the form of improved health and ageing by delaying the onset of age-associated diseases. A common diet-restriction regimen used in experimental animals is a 30% reduction in food intake.
Resveratrol (3,5,49-trihydroxystilbene) extends the lifespan of diverse species including Sacchar... more Resveratrol (3,5,49-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-c coactivator 1a (PGC-1a) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.
Calorie restriction extends lifespan and produces a metabolic profile desirable for treating dise... more Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes 1,2 . SIRT1, an NAD + -dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity 3-9 . Resveratrol, a polyphenolic SIRT1 activator, mimics the antiageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival 10-14 . Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.
Protein-tyrosine phosphatase 1B (PTP-1B) is a major protein-tyrosine phosphatase that has been im... more Protein-tyrosine phosphatase 1B (PTP-1B) is a major protein-tyrosine phosphatase that has been implicated in the regulation of insulin action, as well as in other signal transduction pathways. To investigate the role of PTP-1B in vivo, we generated homozygotic PTP-1B-null mice by targeted gene disruption. PTP-1B-deficient mice have remarkably low adiposity and are protected from diet-induced obesity. Decreased adiposity is due to a marked reduction in fat cell mass without a decrease in adipocyte number. Leanness in PTP-1B-deficient mice is accompanied by increased basal metabolic rate and total energy expenditure, without marked alteration of uncoupling protein mRNA expression. In addition, insulin-stimulated whole-body glucose disposal is enhanced significantly in PTP-1B-deficient animals, as shown by hyperinsulinemic-euglycemic clamp studies. Remarkably, increased insulin sensitivity in PTP-1B-deficient mice is tissue specific, as insulin-stimulated glucose uptake is elevated in skeletal muscle, whereas adipose tissue is unaffected. Our results identify PTP-1B as a major regulator of energy balance, insulin sensitivity, and body fat stores in vivo.
An enhanced metabolic efficiency for accelerating the recovery of fat mass (or catch-up fat) is a... more An enhanced metabolic efficiency for accelerating the recovery of fat mass (or catch-up fat) is a characteristic feature of body weight regulation after weight loss or growth retardation and is the outcome of an "adipose-specific" suppression of thermogenesis, i.e., a feedback control system in which signals from the depleted adipose tissue fat stores exert a suppressive effect on thermogenesis. Using a previously described rat model of semistarvation-refeeding in which catch-up fat results from suppressed thermogenesis per se, we report here that the gene expression of stearoyl-coenzyme A desaturase 1 (SCD1) is elevated in skeletal muscle after 2 wk of semistarvation and remains elevated in parallel to the phase of suppressed thermogenesis favoring catch-up fat during refeeding. These elevations in the SCD1 transcript are skeletal muscle specific and are associated with elevations in microsomal ⌬9 desaturase enzyme activity, in the ⌬9 desaturation index, and in the relative content of SCD1-derived monounsaturates in several lipid fractions extracted from skeletal muscle. An elevated skeletal muscle SCD1, by desaturating the products of de novo lipogenesis and diverting them away from mitochondrial oxidation, would inhibit substrate cycling between de novo lipogenesis and lipid oxidation, thereby leading to a state of suppressed thermogenesis that regulates the body's fat storesA role for skeletal muscle stearoyl-CoA desaturase 1 in control of thermogenesis. FASEB J. 20, E1157-E1170 (2006)
Brown adipose tissue (BAT) has been recognized for more than 20 years to play a key role in cold-... more Brown adipose tissue (BAT) has been recognized for more than 20 years to play a key role in cold-induced non-shivering thermogenesis (CIT, NST), and body weight homeostasis in animals. BAT is a flexible tissue that can be recruited by stimuli (including small molecules in animals), and atrophies in the absence of a stimulus. In fact, the contribution of BAT (and UCP1) to resting metabolic rate and healthy body weight homeostasis in animals (rodents) is now well established. Many investigations have shown that resistance to obesity and associated disorders in various rodent models is due to increased BAT mass and the number of brown adipocytes or UCP1 expression in various depots. The recent discovery of active BAT in adult humans has rekindled the notion that BAT is a therapeutic target for combating obesity-related metabolic disorders. In this review, we highlight investigations performed in rodents that support the contention that activation of BAT formation and/or function in obe...
Mice lacking beta-adrenoceptors, which mediate the thermogenic effects of norepinephrine and epin... more Mice lacking beta-adrenoceptors, which mediate the thermogenic effects of norepinephrine and epinephrine, show diminished thermogenesis and high susceptibility to obesity, whereas mice lacking stearoyl-CoA desaturase 1 (SCD1), which catalyzes the synthesis of monounsaturated fatty acids, show enhanced thermogenesis and high resistance to obesity. In testing whether beta-adrenergic control of thermogenesis might be mediated via repression of the SCD1 gene, we found that in mice lacking beta-adrenoceptors, the gene expression of SCD1 is elevated in liver, skeletal muscle and white adipose tissue. In none of these tissues/organs, however, could a link be found between increased sympathetic nervous system activity and diminished SCD1 gene expression when thermogenesis is increased in response to diet or cold, nor is the SCD1 transcript repressed by the administration of epinephrine. Taken together, these studies suggest that the elevated SCD1 transcript in tissues of mice lacking beta-a...
A new member of the uncoupling protein (UCP) family called UCP3 has recently been cloned and show... more A new member of the uncoupling protein (UCP) family called UCP3 has recently been cloned and shown to be highly expressed in skeletal muscle of rodents and humans. In the present study, UCP3 was overexpressed in C 2 C 12 myoblasts where it acts as an uncoupling protein.
The prevalence of Type 2 diabetes is increasing at an alarming rate in most parts of the world. E... more The prevalence of Type 2 diabetes is increasing at an alarming rate in most parts of the world. Effective therapeutic drugs are urgently needed, not only to control the disease but also to prevent or delay its progression. Therapies that target the underlying pathogenesis could, in theory, hold such potential. Recent evidence strongly suggests that impaired mitochondrial function is part of the underlying pathogenesis of insulin resistance and Type 2 diabetes. Peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC-1alpha) is a transcription co-activator that plays a key role in regulating mitochondrial biogenesis and energy metabolism in multiple tissues. Thus, improvement and restoration of mitochondrial function and oxidative capacity through activation of PGC-1alpha could provide new treatments for metabolic diseases. A diverse array of proteins has been shown to regulate PGC-1alpha transcription and/or activity, some of which represent promising targets for pharmaceutical intervention.
Annual Review of Pharmacology and Toxicology, 2007
The unabated rise in the prevalence of obesity is a challenge for global health care systems. Eff... more The unabated rise in the prevalence of obesity is a challenge for global health care systems. Efforts to reverse this trend by dietary or behavioral counseling have not been successful, which has stimulated efforts to find a role for pharmacotherapy. Currently only a small number of antiobesity drugs are approved for long-term use and only a few compounds are in clinical development. Despite recent progress in the understanding of the regulation of energy balance, drug discovery has been less productive than expected. In the present review, the clinically available antiobesity agents are discussed. Examples of drug candidates that are currently in development are given and the possible future range of antiobesity agents is illustrated by the targets being addressed in drug discovery. Finally, the efficacy of antiobesity agents and their value in the treatment of obesity are assessed in comparison with other therapeutic approaches, such as surgery and changes in lifestyle.
Calorie restriction extends lifespan and produces a metabolic profile desirable for treating dise... more Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes 1,2 . SIRT1, an NAD + -dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity 3-9 . Resveratrol, a polyphenolic SIRT1 activator, mimics the antiageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival 10-14 . Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.
This is a measure of limited dietary energy intake in which the physiological effects are seen in... more This is a measure of limited dietary energy intake in which the physiological effects are seen in the form of improved health and ageing by delaying the onset of age-associated diseases. A common diet-restriction regimen used in experimental animals is a 30% reduction in food intake.
The RR-enantiomer of the beta 3-adrenergic receptor agonist BRL 37344 was tritiated to yield a hi... more The RR-enantiomer of the beta 3-adrenergic receptor agonist BRL 37344 was tritiated to yield a high specific activity compound, [3H]SB 206606. This new, potentially specific, beta 3-adrenergic receptor ligand was characterized by binding studies using membranes from both Chinese hamster ovary K1 cells transfected with the rat beta 3-adrenergic receptor and rat interscapular brown adipose tissue, where beta 1-, beta 2-, and beta 3-adrenergic receptor subtypes are known to coexist. [3H]SB 206606 was found to bind to a single population of binding sites in both preparations. The Kd values for [3H]SB 206606 binding to membranes from Chinese hamster ovary K1 cells and brown adipose tissue were quite comparable (58 and 38 nM, respectively). At 37 degrees, the time courses of association and dissociation of [3H]SB 206606 with membranes of brown adipose tissue were quite short. At 4 degrees, the T1/2 were found to be 13 and 40 min, respectively. The Ki values for various beta-adrenergic ago...
The earliest defect in developing type 2 diabetes is insulin resistance, characterized by decreas... more The earliest defect in developing type 2 diabetes is insulin resistance, characterized by decreased glucose transport and metabolism in muscle and adipocytes. The glucose transporter GLUT4 mediates insulin-stimulated glucose uptake in adipocytes and muscle by rapidly moving from intracellular storage sites to the plasma membrane. In insulin-resistant states such as obesity and type 2 diabetes, GLUT4 expression is decreased in adipose tissue but preserved in muscle. Because skeletal muscle is the main site of insulin-stimulated glucose uptake, the role of adipose tissue GLUT4 downregulation in the pathogenesis of insulin resistance and diabetes is unclear. To determine the role of adipose GLUT4 in glucose homeostasis, we used Cre/loxP DNA recombination to generate mice with adipose-selective reduction of GLUT4 (G4A-/-). Here we show that these mice have normal growth and adipose mass despite markedly impaired insulin-stimulated glucose uptake in adipocytes. Although GLUT4 expression ...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 1998
Endurance exercise training has been shown to decrease diet-induced thermogenesis (DIT) in rats a... more Endurance exercise training has been shown to decrease diet-induced thermogenesis (DIT) in rats and humans. In rodents, most thermogenesis is thought to occur in brown adipose tissue via activation of the uncoupling protein-1 (UCP1) and in skeletal muscle. Since the level of UCP1 mRNA in rat BAT was reported to be unmodified by exercise training, the newly described uncoupling proteins UCP2 and UCP3 could be responsible for the decreased DIT in trained rats. UCP3 mRNA levels in endurance-trained rats were found to be reduced by 76% and 59% in tibialis anterior and soleus muscles, respectively. UCP2 mRNA levels were also decreased in tibialis anterior and in heart by 54% and 41%, respectively. Neither white adipose tissue UCP2 nor brown adipose tissue UCP1, UCP2, and UCP3 mRNA levels were modified. The results of this study show that a need for a higher metabolic efficiency is associated with decreased mRNA expression of the uncoupling proteins in skeletal and heart muscles, which wo...
Glucose homeostasis was investigated in ad libitum fed, young and adult male wild-type, loxTB Mc4... more Glucose homeostasis was investigated in ad libitum fed, young and adult male wild-type, loxTB Mc4r and Sim1-Cre, loxTB Mc4r mice. At 5 weeks of age, loxTB Mc4r mice were significantly hyperglycemic and hyperinsulinemic ( ). Sim1-Cre, loxTB Mc4r mice also had elevated serum glucose and insulin levels, albeit levels were not as high as observed in loxTB Mc4r mice. At 12 weeks of age, loxTB Mc4r mice developed severe hyperinsulinemia with increased glucose levels. Sim1-Cre, loxTB Mc4r mice, however, were normoglycemic, but still had significantly elevated insulin levels ( ). These data indicate that PVH and/or amygdala Mc4r re-expression can ameliorate the profound loxTB Mc4r diabetes, but that MC4Rs in other areas may contribute to the regulation of melanocortin-mediated regulation of glucose homeostasis. However, given the altered body composition of Sim1-Cre, loxTB Mc4r mice compared with wild-type mice and loxTB Mc4r mice, and the known effects of increased fat stores on type 2 diabetes, caution must be used when interpreting the insulin/glucose homeostasis data.
0 ]. cDNAs were further amplified using the following primers: [5 0 -CGC TCG AGT GCA GAA TTC-3 0 ... more 0 ]. cDNAs were further amplified using the following primers: [5 0 -CGC TCG AGT GCA GAA TTC-3 0 ] and [5 0 -GCC GCT CGA GTG CAG AT TCN NNN NCG AGA-3 0 ]. Primers were designed based on ref. 13, with modification to minimize the likelihood of inadvertently favouring the amplification of any specific known plant DNA sequence(s). The resulting cDNAs were further amplified by PCR using primers: 5 0 -AAC AGG GTA CGG TGG AAG TG-3 0 and 5 0 -ATC CTC CAG TAC CAG GAA GC-3 0 , which correspond to nucleotide positions 395 to 675 of dehydrin DHN1 (GenBank accession no. X63061) 12 . The resultant PCR product was cloned into TOPO TA cloning vector (Invitrogen) and sequenced.
An enhanced metabolic efficiency for accelerating the recovery of fat mass (or catch-up fat) is a... more An enhanced metabolic efficiency for accelerating the recovery of fat mass (or catch-up fat) is a characteristic feature of body weight regulation after weight loss or growth retardation and is the outcome of an "adipose-specific" suppression of thermogenesis, i.e., a feedback control system in which signals from the depleted adipose tissue fat stores exert a suppressive effect on thermogenesis. Using a previously described rat model of semistarvation-refeeding in which catch-up fat results from suppressed thermogenesis per se, we report here that the gene expression of stearoyl-coenzyme A desaturase 1 (SCD1) is elevated in skeletal muscle after 2 wk of semistarvation and remains elevated in parallel to the phase of suppressed thermogenesis favoring catch-up fat during refeeding. These elevations in the SCD1 transcript are skeletal muscle specific and are associated with elevations in microsomal ⌬9 desaturase enzyme activity, in the ⌬9 desaturation index, and in the relative content of SCD1-derived monounsaturates in several lipid fractions extracted from skeletal muscle. An elevated skeletal muscle SCD1, by desaturating the products of de novo lipogenesis and diverting them away from mitochondrial oxidation, would inhibit substrate cycling between de novo lipogenesis and lipid oxidation, thereby leading to a state of suppressed thermogenesis that regulates the body's fat storesA role for skeletal muscle stearoyl-CoA desaturase 1 in control of thermogenesis. FASEB J. 20, E1157-E1170 (2006)
The neural pathways through which central serotonergic systems regulate food intake and body weig... more The neural pathways through which central serotonergic systems regulate food intake and body weight remain to be fully elucidated. We report that serotonin, via action at serotonin1B receptors (5-HT 1B Rs), modulates the endogenous release of both agonists and antagonists of the melanocortin receptors, which are a core component of the central circuitry controlling body weight homeostasis. We also show that serotonin-induced hypophagia requires downstream activation of melanocortin 4, but not melanocortin 3, receptors. These results identify a primary mechanism underlying the serotonergic regulation of energy balance and provide an example of a centrally derived signal that reciprocally regulates melanocortin receptor agonists and antagonists in a similar manner to peripheral adiposity signals.
This is a measure of limited dietary energy intake in which the physiological effects are seen in... more This is a measure of limited dietary energy intake in which the physiological effects are seen in the form of improved health and ageing by delaying the onset of age-associated diseases. A common diet-restriction regimen used in experimental animals is a 30% reduction in food intake.
Resveratrol (3,5,49-trihydroxystilbene) extends the lifespan of diverse species including Sacchar... more Resveratrol (3,5,49-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-c coactivator 1a (PGC-1a) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.
Calorie restriction extends lifespan and produces a metabolic profile desirable for treating dise... more Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes 1,2 . SIRT1, an NAD + -dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity 3-9 . Resveratrol, a polyphenolic SIRT1 activator, mimics the antiageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival 10-14 . Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.
Protein-tyrosine phosphatase 1B (PTP-1B) is a major protein-tyrosine phosphatase that has been im... more Protein-tyrosine phosphatase 1B (PTP-1B) is a major protein-tyrosine phosphatase that has been implicated in the regulation of insulin action, as well as in other signal transduction pathways. To investigate the role of PTP-1B in vivo, we generated homozygotic PTP-1B-null mice by targeted gene disruption. PTP-1B-deficient mice have remarkably low adiposity and are protected from diet-induced obesity. Decreased adiposity is due to a marked reduction in fat cell mass without a decrease in adipocyte number. Leanness in PTP-1B-deficient mice is accompanied by increased basal metabolic rate and total energy expenditure, without marked alteration of uncoupling protein mRNA expression. In addition, insulin-stimulated whole-body glucose disposal is enhanced significantly in PTP-1B-deficient animals, as shown by hyperinsulinemic-euglycemic clamp studies. Remarkably, increased insulin sensitivity in PTP-1B-deficient mice is tissue specific, as insulin-stimulated glucose uptake is elevated in skeletal muscle, whereas adipose tissue is unaffected. Our results identify PTP-1B as a major regulator of energy balance, insulin sensitivity, and body fat stores in vivo.
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Papers by Olivier Boss