Systemic nicotine alters whole-body fat utilization in female rats

Cigarette smoking produces weight suppression in humans that often rebounds following smoking cessation. Nicotine (NIC) administration produces similar effects in rats. While changes in food intake are thought to account for some of the body weight changes, few reports have investigated how NIC affects whole-body metabolism. In the present study, measures of respiratory quotient (RQ) and energy expenditure (EE) were used to investigate metabolic changes that may contribute to NIC's effects on body weight. Female rats (n=46) were implanted for 14 days with subcutaneous Alzet minipumps containing NIC (6 mg/kg/day) or its vehicle. One-hour metabolic test sessions occurred four times: 2 and 12 days after pump implant and 2 and 8 days after pump removal. NIC initially suppressed body weight gain, followed by steady recovery that was briefly exaggerated after withdrawing NIC. Daily food intake was acutely suppressed by NIC and acutely potentiated after NIC cessation. RQ, but not EE, was suppressed by NIC 2 days after pump implant indicating increased fat utilization. Conversely, RQ was increased 2 days after pump removal signaling increased fat storage. These findings indicate that acute changes in whole-body metabolism may contribute to the weight modulating effects of NIC.     

Cosmetic Mesotherapy: Between Scientific Evidence,Science Fiction,and Lucrative Business

Mesotherapy, originally conceived in Europe, is a minimally invasive technique that consists of the intra- or subcutaneous injection of variable mixtures of natural plant extracts, homeopathic agents, pharmaceuticals, vitamins, and other bioactive substances in microscopic quantities through dermal multipunctures. Its application in cosmetic medicine and surgery is gaining in popularity and acceptance and is rapidly growing in profile at an alarming rate. Despite their attraction as purported rejuvenating and ‘‘fat-dissolving’’ injections, the safety and efficacy of these novel cosmetic treatments remain ambiguous, making mesotherapy vulnerable to criticism by the generally more skeptical medical community. The technique is shrouded in mystery and the controversy surrounding it pertains to its efficacy and potential adverse effects that are subject of much concern. As with any new technology, it is important to assess the benefits, safety, experience, and standardization of mesotherapy. More studies are necessary before it can be advocated as a safe and effective treatment for body contouring and facial rejuvenation. Although the claims made about mesotherapy may be hard to believe at face value, we must be cautious about rejecting new ideas. Just as absence of proof is not proof of absence, lack of scientific validation is not proof that it does not work.     

Effects of arecoline on adipogenesis, lipolysis, and glucose uptake of adipocytes—A possible role of betel-quid chewing in metabolic syndrome

To investigate the possible involvement of betel-quid chewing in adipocyte dysfunction, we determined the effects of arecoline, a major alkaloid in areca nuts, on adipogenic differentiation (adipogenesis), lipolysis, and glucose uptake by fat cells. Using mouse 3T3-L1 preadipocytes, we showed that arecoline inhibited adipogenesis as determined by oil droplet formation and adipogenic marker gene expression. The effects of arecoline on lipolysis of differentiated 3T3-L1 adipocytes were determined by the glycerol release assay, indicating that arecoline induced lipolysis in an adenylyl cyclase-dependent manner. The diabetogenic effects of arecoline on differentiated 3T3-L1 adipocytes were evaluated by the glucose uptake assay, revealing that ≥ 300 µM arecoline significantly attenuated insulin-induced glucose uptake; however, no marked effect on basal glucose uptake was detected. Moreover, using 94 subjects that were randomly selected from a health check-up, we determined the association of betel-quid chewing with hyperlipidemia and its related risk factors. Hyperlipidemia frequency and serum triglyceride levels of betel-quid chewers were significantly higher than those of non-betel-quid chewers. In this study, we demonstrated that arecoline inhibits adipogenic differentiation, induces adenylyl cyclase-dependent lipolysis, and interferes with insulin-induced glucose uptake. Arecoline-induced fat cell dysfunction may lead to hyperlipidemia and hyperglycemia/insulin-resistance. These findings provide the first in vitro evidence of betel-quid chewing modulation of adipose cell metabolism that could contribute to the explanation of the association of this habit with metabolic syndrome disorders.     

The impact of catecholamines on skeletal muscle following massive burns: Friend or foe?

Profound skeletal muscle wasting in the setting of total body hypermetabolism is a defining characteristic of massive burns, compromising the patient’s recovery and necessitating a protracted period of rehabilitation. In recent years, the prolonged use of the non-selective beta-blocker, propranolol, has gained prominence as an effective tool to assist with suppressing epinephrine-dependent burn-induced hypermetabolism and by extension, blunting muscle catabolism. However, synthetic β-adrenergic agonists, such as clenbuterol, are widely associated with the promotion of muscle growth in both animals and humans. Moreover, experimental adrenodemedullation is known to result in muscle catabolism. Therefore, the blunting of muscle β-adrenergic signaling via the use of propranolol would be expected to negatively impair muscle protein homeostasis. This review explores these paradoxical observations and identifies the manner by which propranolol is thought to exert its anti-catabolic effects in burn patients. Moreover, we identify potential avenues by which the use of beta-blocker therapy in the treatment of massive burns could potentially be further refined to promote the recovery of muscle mass in these critically ill patients while continuing to ameliorate total body hypermetabolism.     

Metabolic effects of newly synthesized phosphodiesterase-3 inhibitor 6-[4-(4-methylpiperidin-1-yl)-4-oxobutoxy]-4-methylquinolin-2(1H)-one on rat adipocytes

Background

Clinical use of selective PDE3 inhibitors as cardiotonic agents is limited because of their chronotropic and lipolytic side effects. In our previous work, we synthesized a new PDE3 inhibitor named MC2 (6-[4-(4-methylpiperidin-1-yl)-4-oxobutoxy]-4-methylquinolin-2(1H)-one) which produced a high positive inotropic action with a negative chronotropic effect. This work was done to evaluate the effects of MC2 on adipocytes and compare its effects with those of amrinone and cilostamide.

Methods

Preadipocytes were isolated from rat adipose tissue and differentiated to adipocyte in the presence of cilostamide, amrinone or MC2. Lipolysis and adipogenesis was evaluated by measuring glycerol level and Oil Red O staining, respectively. Adipocyte proliferation and apoptosis were determined with MTT assay and Annexin V/PI staining, respectively.

Results

Differentiation to adipocyte was induced by amrinone but not by cilostamide or MC2. Basal and isoproterenol-stimulated lipolysis significantly increased by cilostamide (p < 0.05). Similarly, amrinone enhanced the stimulated lipolysis (p < 0.01). On the other hand, MC2 significantly decreased both adipogenesis (p < 0.05) and stimulated lipolysis (p < 0.001). Also, incubation of differentiated adipocytes with MC2 caused the loss of cell viability, which was associated with the elevation in apoptotic rate (p < 0.05).

Conclusion

Our data indicate that selective PDE3 inhibitors produce differential effects on adipogenesis and lipolysis. MC2 has proapoptotic and antilipolytic effects on adipocytes and does not stimulate adipogenesis. Therefore, in comparison with the clinically available selective PDE3 inhibitors, MC2 has lowest metabolic side effects and might be a good candidate for treatment of congestive heart failure.     

Anti-obesity action of INDUS810, a natural compound from Trigonella foenum-graecum: AMPK-dependent lipolysis effect in adipocytes

ObjectiveWe investigated the anti-obesity effect and underlying action mechanism of INDUS810 isolated from Trigonella foenum-graecum L. (Fabaceae), an annual herb commonly known as fenugreek and reported to have hypocholesterolemic, antidiabetic, anticancer and gastroprotective properties.MethodsFor obese animal study, 4-week old mice were fed with normal diet or high-fat diet together with or without intraperitoneal injection of INDUS810 (200 mg/kg) twice per week for 15 weeks. 3T3-L1 cells were used to study action mechanism of INDUS810 in adipocyte differentiation and lipid metabolism.ResultsWe found that INDUS810 can reduce high-fat diet-induced weight increase in epididymal white adipose tissue, interscapular brown adipose tissue and liver, as well as serum levels of total cholesterol and low-density lipoprotein cholesterol. Moreover, the insulin sensitivity was significantly improved in INDUS810-treated obese mice. In 3T3-L1 adipocytes, we found that INDUS810 could inhibit lipid accumulation at either differentiating or mature stages, and increase lipolysis activity in mature adipocytes. Additionally, INDUS810 has no effects on cell viability nor the expressions of adipocyte differentiation markers like fatty acid synthase, peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein α. In contrast, INDUS810 can increase protein levels of peroxisome proliferator-activated receptor α, peroxisome-proliferator-activated receptor-γ co-activator 1β, sirtuin 1 and sirtuin 3. Of note, INDUS810 can activate adenosine monophosphate-activated protein kinase, which leads to the reduction of lipid contents in adipocytes.ConclusionOur in vitro and in vivo studies suggest that INDUS810 is a potential anti-obesity agent, and this action depends on activate adenosine monophosphate-activated protein kinase activation.     

Stimulation of cyclic adenosine 3′,5′-monophosphate accumulation and lipolysis in fat cells by adenosine deaminase

Summary The basal lipolytic activity of isolated fat cells of the rat was greatly enhanced in the presence of 0.01 to 30 g adenosine deaminase (ADA) per ml. This effect was more pronounced in dilute (20000 cells/ml) than in concentrated cell suspensions (100000 cells/ml); this is possibly due to the presence, in the incubation medium, of a high concentration of inosine which is formed by the deamination of the large amounts of adenosine released from high concentrations of fat cells. Inosine, although less potent than adenosine as an antilipolytic agent, markedly inhibited ADA-induced lipolysis at concentrations between 10 to 100 M. The lipolytic effect of ADA was identical with the stimulation of lipolysis by 1 M noradrenaline or 1 mM theophylline, while 1 mM dibutyryl cyclic AMP yielded two-fold higher values. The effects of ADA and lipolytic agents at maximally stimulating concentrations were not additive.After 5 min of incubation maximally effective concentrations of ADA which were also maximal with respect to lipolysis caused a 3- to 6-fold elevation of cyclic AMP levels in fat cells. A similar increase was observed with maximally effective concentrations of theophylline, whereas noradrenaline produced a 100- to 200-fold elevation. This indicates that a small accumulation of cyclic AMP may be sufficient to trigger the full lipolytic response. Furthermore, ADA, like theophylline, acted synergistically with noradrenaline and prevented the fall of cyclic AMP levels during 30 min of incubation.Insulin (100 U/ml) and nicotinic acid (0.1 M) decreased cyclic AMP accumulation and glycerol production induced by ADA.The results support the hypothesis that adenosine is released from isolated fat cells and that this nucleoside may serve as an inhibitor of adenyl cyclase activity, thus regulating cyclic AMP-dependent processes in adipose tissue.     

Activation and inhibition of lipolysis in isolated fat cells by various inhibitors of cyclic AMP phosphodiesterase

Summary The effects of methylxanthines, papaverine, dipyridamole and imipramine on lipolysis and phosphodiesterase activity of rat adipose tissue were investigated. Lipolysis in isolated fat cells was stimulated by theophylline and caffeine whereas papaverine, dipyridamole and imipramine had no substantial effect on the basal lipolytic rate. Lipolysis induced by noradrenaline was potentiated by theophylline, but blocked by papaverine, dipyridamole and imipramine at concentrations between 0.02 to 0.2 mM. These agents also depressed lipolysis induced by theophylline and dibutyryl cyclic AMP and reduced the lipolytic activity of homogenates of adipose tissue. The activity of phosphodiesterase assayed over a wide range of substrate concentrations revealed two different Michaelis constants. Both types of phosphodiesterase were inhibited by theophylline, papaverine, dipyridamole and imipramine in a competitive manner, the low K _m enzyme being more sensitive for inhibition than the high K _m enzyme. On both types of phosphodiesterase papaverine and dipyridamole proved to be 10 to 100 times more potent inhibitors than theophylline and imipramine. To explain the antilipolytic effect of phosphodiesterase inhibitors it is assumed that they do not only affect substrate binding of cyclic AMP to phosphodiesterase but also displace cyclic AMP from the binding site on protein kinase, thus acting as inhibitors of the activation process within the lipolytic system.     

Ketonuria after fasting may be related to the metabolic superiority

Obese individuals are less able to oxidize fat than non-obese individuals. Caloric reduction or fasting can detect ketonuria. We investigated the differences of metabolic parameters in the presence of ketonuria after a minimum 8 hr fast in a cross-sectional analysis of 16,523 Koreans (6,512 women and 10,011 men). The relationship between the presence of ketonuria of all subjects and prevalence of obesity, central obesity, metabolic syndrome, and obesity-related metabolic parameters were assessed. The ketonuria group had lower prevalence of obesity, central obesity, and metabolic syndrome than the non-ketonuria group. In addition, all metabolic parameters (including body weight, waist circumference, blood glucose, high-density lipoprotein, triglyceride, blood pressure, and insulin) were favorable in the ketonuria group than in the non-ketonuria group, even after adjustment for age, tobacco use, and alcohol consumption. The odds ratios of having obesity (odds ratio [OR]=1.427 in women, OR=1.582 in men, P<0.05), central obesity (OR=1.675 in women, OR=1.889 in men, P<0.05), and metabolic syndrome (OR=3.505 in women, OR=1.356 in men, P<0.05) were increased in the non-ketonuria group compared to the ketonuria group. The presence of ketonuria after at least an 8 hr fast may be indicative of metabolic superiority.     

Activation of muscarinic M-3 receptor may decrease glucose uptake and lipolysis in adipose tissue of rats

Role of muscarinic receptor in the regulation of glucose uptake or lipolysis in adipose tissue remained unclear. In epididymal white adipose tissue (WAT) isolated from Wistar rats, we observed that acetylcholine (ACh) attenuated the insulin-stimulated glucose uptake and the release of glycerol from WAT in a concentration-dependent manner. Using the blockade of specific antagonists, both actions of ACh were characterized mainly due to an activation of M3 receptors. In the presence of various inhibitors for PLC–PKC pathway, ACh-decreased glucose uptake was also reversed. Taken together, these results suggest that muscarinic M3 receptor is involved in the regulation of glucose uptake and/or lipolysis in adipose tissue.