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PubMed2000

Reduced hormone-sensitive lipase activity is not a major metabolic defect in Finnish FCHL families.

The pathogenetic mechanisms behind familial combined hyperlipidemia (FCHL) are unknown. However, exaggerated postprandial lipemia and excessive serum free fatty acid (FFA) concentrations have drawn attention to altered lipid storage and lipolysis in peripheral adipose tissue. Hormone-sensitive lipase (HSL) is the enzyme responsible for intracellular lipolysis in adipocytes and a decrease of adipocyte HSL activity has been demonstrated in Swedish FCHL subjects. The aim of the study was to investigate if adipose tissue HSL activity had any effect on lipid phenotype and if low HSL activity and FCHL were linked in Finnish FCHL families. A total of 48 family members from 13 well-characterized Finnish FCHL families and 12 unrelated spouses participated in the study. FCHL patients with different lipid phenotypes (IIA, IIB, IV) did not differ in adipose tissue HSL activity from each other or from the 12 normolipidemic spouses (P = 0.752). In parametric linkage analysis using an affecteds-only strategy the low adipose tissue HSL activity was not significantly linked with FCHL phenotype. However, we found a significant sibling-sibling correlation for the HSL trait (0.51, P < 0.01). Thus, a modifying or interacting role of HSL in the pathogenesis of FCHL could not be excluded.

Adipose Tissue↗
PubMed1999

Altered cord serum lipid levels associated with small for gestational age infants.

OBJECTIVE: To determine whether small for gestational age (SGA) infants show changes in lipid metabolism that could distinguish growth-restricted subpopulations. METHODS: Sera from the arterial cord blood from 38 SGA infants were analyzed for apolipoprotein A-I level, total lipid content, and distribution of those lipids as triglycerides, diglycerides, free fatty acids, and phospholipids. Comparisons were made between appropriate for gestational age (AGA) controls (n = 25), SGA infants with a ponderal index below the tenth percentile (SGA I, n = 20), and SGA infants with a ponderal index above the tenth percentile (SGA II, n = 18). RESULTS: Total cord serum lipid content was markedly decreased in all SGA infants compared with AGA infants (2.8 times lower). Although SGA infants showed total lipid concentration decreases, SGA I and SGA II infants showed distinct characteristics. Infants in the SGA I group had higher triglyceride levels (1.8 times higher) and lower free fatty acid levels (1.4 times lower), compared with AGA infants (P < .001). The lipid subclass distribution in SGA II infants was not significantly different from that in AGA infants, with the exception of an increase in triglyceride concentrations (1.3 times higher). Although the 22-kD placenta-derived apolipoprotein A-I was similar in all groups, the level of fetal liver-derived 28-kD apolipoprotein A-I was 6.5 times lower in SGA I infants than in AGA or SGA II infants (P < .001). CONCLUSION: The SGA I infants appeared to have impaired utilization of circulating triglycerides, consistent with peripheral adipose depletion. Diminished fetus-derived apolipoprotein A-I levels with normal levels of placenta-derived apolipoprotein A-I levels might indicate a defect in the production or secretion of apolipoproteins associated with growth restriction.

Fetal Blood↗
PubMed1999

Feeding and body-weight regulation by hypothalamic neuropeptides--mediation of the actions of leptin.

Neuropeptides are essential for the regulation of appetite and body weight within the hypothalamus. The understanding of the neuropeptide regulation of energy homeostasis has been greatly advanced by the recent discovery of leptin, the protein product of the obese gene (ob). Significant new insights into the relationship between peripheral adiposity signals and their impact on the hypothalamic neuropeptide signaling circuitry have provided some crucial missing links in the negative-feedback regulation of appetite and body weight. The neuropeptide Y orexigenic network is a final common pathway for this signaling cascade and, along with feeding-inhibitory neuropeptides such as melanocortin, corticotropin-releasing factor and glucagon-like peptide 1, it is a major target through which leptin exerts a regulatory tonic restraint on body adiposity.

Animals↗
PubMed1997

Subcutaneous, omentum and tumor fatty acid composition, and serum insulin status in patients with benign or cancerous ovarian or endometrial tumors. Do tumors preferentially utilize polyunsaturated fatty acids?

The relationships between the fatty acid composition of cancerous endometrium and ovary, and peripheral adipose tissues were studied in Israeli Jewish women, and are presented together since no differences were shown between them. The results suggest a mobilization of linoleic acid from subcutaneous and omental depots and its incorporation into tumors accompanied by a high degree of desaturation. High blood insulin concentrations characterized patients with stage I and II disease, and low concentrations characterized patients with advanced degrees of malignancy.

Adipose Tissue↗
PubMed1995

Currently available hypolipidaemic drugs and future therapeutic developments.

Dyslipidaemia may be treated with a number of safe and effective pharmacological agents that target specific lipid disorders through a variety of mechanisms. The bile-acid sequestrants--cholestyramine and colestipol--primarily decrease LDL cholesterol by binding bile acids, thereby decreasing intrahepatic cholesterol, and by increasing the activity of LDL receptors. Nicotinic acid lowers LDL cholesterol and triglyceride by decreasing VLDL synthesis and by decreasing free fatty acid mobilization from peripheral adipocytes. The HMG-CoA reductase inhibitors--fluvastatin, lovastatin, pravastatin and simvastatin--lower LDL cholesterol by partially inhibiting HMG-CoA reductase (the rate-limiting enzyme of cholesterol biosynthesis) and by increasing the activity of LDL receptors. The fibric-acid derivatives--bezafibrate, ciprofibrate, clofibrate, fenofibrate and gemfibrozil--primarily decrease triglyceride by increasing lipoprotein lipase activity and by decreasing the release of free fatty acids from peripheral adipose tissue. Probucol decreases LDL cholesterol by increasing non-receptor-mediated LDL clearance; as an anti-oxidant, probucol also decreases LDL oxidation; oxidized LDL which is thought to lead to atherogenesis. Although these agents have been proven safe in clinical trials, like any drug, they carry the risk for adverse effects. The bile-acid sequestrants may cause constipation, reflux oesophagitis, and dyspepsia, and may bind coadministered medications such as digitalis glycosides, beta blockers, warfarin, and exogenous thyroid hormone. Nicotinic acid use is commonly associated with flushing and pruritus and may also cause non-specific gastrointestinal complaints, hepatotoxicity (hepatic necrosis, hepatitis, or elevated liver enzymes), gout, myolysis, decreased glucose tolerance and increased fasting glucose levels, and ophthalmological complications including decreased visual acuity, toxic amblyopia, and cystic maculopathy. The HMG-CoA reductase inhibitors may produce liver enzyme elevations, creatine kinase elevations and rhabdomyolysis. The combination of a reductase inhibitor and a fibrate increases the risk for rhabdomyolysis. Possible adverse effects of the fibric-acid derivatives include abdominal discomfort, nausea, flatulence, increased lithogenicity of bile, liver enzyme elevations and creatine kinase elevations. Probucol may increase the QTc interval and may cause non-specific gastrointestinal complaints.

Anticholesteremic Agents↗
PubMed1997

Anthropometric characteristics of healthy Italian nonagenarians and centenarians.

Available anthropometric reference values for elderly people do not include specific norms for over-90-year-old subjects despite their increasing number. In the present study, weight, height and a number of anthropometric variables related to body muscle and fat mass were collected from fifty-seven nonagenarian and forty-one centenarian healthy, non-institutionalized subjects living in an Italian area. Recumbent anthropometry was used to avoid errors associated with impaired mobility. Nonagenarians and centenarian men were taller and heavier than women of corresponding age and had a greater amount of muscle and trunk fat, whereas women showed a marked peripheral adipose distribution. Anthropometric values of both age-groups were generally lower than published norms for 70-89-year-old American and European elderly people. However, differences were less marked when comparing Italian nonagenarians and centenarians with French and British people aged 85 years and over than when comparing Italian subjects with American octogenarians and younger European elderly people. Taken together these findings suggest a dramatic loss of muscle and fat mass in over-90-year-old subjects with respect to younger elderly people. However, changes between successive generations and geographical influences cannot be excluded. The need for local and age-specific norms in nutritional assessment of over-90-year-old people is emphasized. It is also suggested that current anthropometric indices may not be reliable when evaluating the oldest elderly subjects.

Aged↗
PubMed2000

Hormonal regulation of energy partitioning.

A loop system exists between hypothalamic neuropeptide Y (NPY) and peripheral adipose tissue leptin to maintain normal body homeostasis. When hypothalamic NPY levels are increased by fasting or by intracerebroventricular (i.c.v.) infusion, food intake and body weight increase. NPY has genuine hormono-metabolic effects. It increases insulin and corticosterone secretion relative to controls. These hormonal changes, acting singly or combined, favor adipose tissue lipogenic activity, while producing muscle insulin resistance. They also promote leptin release from adipose tissue. When infused i.c.v. to normal rats to mimic its central effects, leptin decreases NPY levels, thus food intake and body weight. Leptin i.c.v. has also genuine hormono-metabolic effects. It decreases insulinemia and adipose tissue storage ability, enhancing glucose disposal. Leptin increases the expression of uncoupling proteins (UCP-1, -2, -3) and thus energy dissipation. Leptin-induced changes favor oxidation at the expense of storage. Circadian fluctuations of NPY and leptin levels maintain normal body homeostasis. In animal obesity, defective hypothalamic leptin receptor activation prevent leptin from acting, with resulting obesity, insulin and leptin resistance.

Adipose Tissue↗
PubMed1996

The loop system between neuropeptide Y and leptin in normal and obese rodents.

Over the years, the work of research laboratories in Baton Rouge (USA), Seattle (USA) and Geneva (Switzerland) have reached analogous conclusions regarding the main etiology of obesity as studied in animals: it largely lies within the brain, notably within the hypothalamus. The hypothalamus is indeed known to modulate food intake and energy partitioning, while the periphery has also been proposed to feed-back on the central nervous system (CNS) to provide information on the state of body energy stores, the two together constituting a loop system connecting the brain to the periphery (1,2,3). This etiologic viewpoint of a pivotal role of the hypothalamus in obesity syndromes has been strengthened by the discovery of one hypothalamic neuropeptide and one peripheral (adipose tissue) hormone, respectively neuropeptide Y (4), and quite particularly, leptin (5). As neuropeptide Y produces hyperphagia (6, 7) and as leptin produces hypophagia in normal animals (8,9,10), the loop system just mentioned was thought to comprise functional relationships, at least between these two factors. Other evidence also suggested that such a loop system was altered in obese animals.

Animals↗
PubMed2000

Ritonavir increases the level of active ADD-1/SREBP-1 protein during adipogenesis.

OBJECTIVE: A novel lipodystrophy syndrome characterized by truncal adiposity, peripheral fat atrophy, type 2 diabetes mellitus, and dyslipidemia occurs in HIV-infected individuals, and may be aggravated by HIV-1 protease inhibitors. The increase in truncal fat could be due to enhanced preadipocyte differentiation. Using the 3T3-L1 preadipocyte model, we reported that ritonavir enhances adipocyte differentiation in culture. The goal of this study was to characterize the molecular mechanism of ritonavir on preadipocyte differentiation. DESIGNS AND METHODS: Time course studies of 3T3-L1 preadipocytes placed in standard differentiation medium (insulin, dexamethasone, and isobutylmethylxanthine) were performed. Glycerol phosphate dehydrogenase (GPDH) was assayed enzymatically, and triacylglycerol (TG) mass was quantified. The adipogenic transcription factors adipocyte determination and differentiation-dependent factor 1 (ADD-1)/sterol regulatory element binding protein 1 (SREBP-1), CCAAT/enhancer-binding protein-alpha (CEBPalpha), and peroxisome proliferator activated receptor-gamma (PPARgamma), were measured by Western analysis. RESULTS: Ritonavir (10 microg/ml) enhanced 3T3-L1 preadipocyte differentiation (30% increase in TG mass; 50% increase in GPDH activity), and transiently raised levels of the 68 kDa active mature form of ADD-1/SREBP-1 during adipogenesis by threefold, compared with standard differentiation. In contrast, ritonavir attenuated the differentiation-induced increase in CEBPalpha and PPARgamma. CONCLUSIONS: Our data suggest that ritonavir enhances 3T3-L1 adipogenesis by increasing the level of active mature ADD-1/SREBP-1. This effect may be due to reduced proteolysis of ADD-1/SREBP-1, as ritonavir inhibits an N-acetyl-leucyl-leucyl-norleucinal (ALLN)-sensitive proteosomal degradation pathway in lymphocytes, and ALLN itself inhibits the breakdown of mature ADD-1/SREBP-1. As mature ADD-1/SREBP-1 regulates several lipogenic enzymes, higher levels may explain the effect of ritonavir on TG accumulation and GPDH activity. Studying ADD-1/SREBP-1 may lead to better understanding and prevention of the lipodystrophy syndrome.

Adipocytes↗
PubMed1987

The early biochemical and hormonal profile of patients with long bone fractures at risk of fat embolism syndrome.

Free fatty acids (FFA) are believed to play a role in the genesis of the fat embolism syndrome (FES). Levels of plasma FFA, glucose, insulin, and the stress hormones cortisol, growth hormone, prolactin, glucagon, and catecholamines were measured on admission to hospital in: a) 14 patients with long bone fractures at risk of developing FES, b) 14 patients with soft-tissue injuries of comparable severity, and c) 20 healthy fasting subjects. The findings were similar in both groups of injured patients and in keeping with the hormonal and substrate responses to the stress of trauma; plasma FFA levels were raised but in neither group was the rise pronounced. Plasma FFA levels of the fracture patients were only moderately higher than the values of the healthy fasting subjects. These findings suggest that mobilized FFA from peripheral adipose tissue are not important in the genesis of the FES, but do not exclude a role for FFA derived mainly from hydrolysis of triglyceride emboli in the lung.

Adolescent↗
PubMed2004

Cellular angiofibroma and related fibromatous lesions of the vulva: report of a series of cases with a morphological spectrum wider than previously described.

AIMS: Cellular angiofibroma (CA) is a rare benign mesenchymal lesion with a predilection for the vulval region. In this report we aim to describe the clinical, pathological and immunohistochemical features of a series of vulval mesenchymal lesions, some of which have the classically described histological appearance of CA while others exhibit atypical features. We believe these lesions fall within the broad spectrum of fibromatous lesions of the vulva. METHODS AND RESULTS: Seven cases were included. Histological sections were examined and immunohistochemical staining with vimentin, desmin, alpha smooth muscle actin, h-caldesmon, S100, EMA, AE1/3, CD34, CD10, ER, PR and MIB1 was performed. The patients' ages ranged from 20 to 65 years and the lesions ranged in size from 10 to 50 mm. All lesions were well circumscribed, moderately cellular lesions and were composed of bland spindle-shaped cells set in a fibrous stroma. Many blood vessels with thick hyalinized walls were present in four cases, in one case occasional such blood vessels were present and in two cases vessels with thick hyalinized walls were not present. In five cases the vessels were at least focally dilated resulting in a haemangiopericytomatous pattern. Histological features identified in a variable numbers of cases included peripheral adipose tissue (four cases), adipose tissue within the centre of the lesion (one case), stromal mast cells (six cases), stromal lymphoid aggregates (five cases), scattered multinucleate cells (five cases), hypocellular hyalinized areas (two cases), myxoid areas (four cases) and focal areas of marked cellular atypia reminiscent of symplastic change within a uterine leiomyoma (one case). Mitotic figures were identified in four cases, all with a mitotic count of < 1 per 10 high-power fields. Immunohistochemically all neoplasms were positive with vimentin and all but one with ER and PR (PR staining was not performed in one tumour). In all cases desmin, alpha smooth muscle actin, h-caldesmon, S100 and AE1/3 were negative (h-caldesmon and AE1/3 staining were not performed in one case). Three cases were positive with CD34, one with EMA and two with CD10. All exhibited a low MIB1 proliferation index of approximately 1%. One lesion recurred locally 6 months following initial removal. CONCLUSIONS: CA is a rare benign vulval mesenchymal lesion with limited potential for local recurrence. We describe several hitherto unreported histological features which add to the morphological spectrum. Although not all lesions exhibit the classically described histological features of CA, we believe all fall within the broad spectrum of benign vulval fibromatous lesions. These cases are characterized by vimentin positivity but negative staining with smooth muscle markers which assists in excluding many of the other vulvovaginal mesenchymal lesions which enter into the differential diagnosis. The immunophenotype indicates that CA probably exhibits fibroblastic rather than myofibroblastic differentiation. These lesions are almost always positive with ER and PR, suggesting that they probably arise from the hormone receptor-positive subepithelial mesenchymal layer within the lower female genital tract.

Adult↗
PubMed1990

Effect of weight cycling on susceptibility to dietary obesity.

Weight cycling, defined as repeated episodes of weight loss followed by weight regain, has been suggested to make rats more energy efficient and produce a state of energy balance favoring accumulation of excess body fat. In addition, weight cycling may favor accumulation of fat in central vs. peripheral adipose depots. In the present study, we gave two groups of female Wistar rats ad libitum access to an obesity-producing high-fat diet (60% of calories from fat). Both groups had previously eaten a low-fat stock diet, but one group had been subjected to three bouts of weight cycling. Rats that were previously weight cycled gained less body weight and body fat when given the high-fat diet than did controls. The lower rate of weight gain was due to a lesser increase in food intake, since daily energy expenditure was significantly lower in previously cycled rats than in controls. In summary, weight cycling does not appear to predispose rats to becoming obese on a high-calorie diet and apparently produces some effect on food intake that reduces, at least in the short run, weight gain on the high-calorie diet.

Adipose Tissue↗
PubMed1996

Role of Lp A-I and Lp A-I/A-II in cholesteryl ester transfer protein-mediated neutral lipid transfer. Studies in normal subjects and in hypertriglyceridemic patients before and after fenofibrate therapy.

The two major subclasses of HDL contain apo A-I only (Lp A-I) or both apo A-I and apo A-II (Lp A-I/A-II). We have carried out experiments to quantify the participation of Lp A-I and Lp A-I/A-II in the neutral lipid transfer reaction in normal and hypertriglyceridemic subjects. Thirteen hypertriglyceridemic subjects were studied before and after fenofibrate therapy. Fenofibrate treatment resulted in decreases in total cholesterol, triglycerides (TG), and VLDL cholesterol of 19%, 48%, and 70%, respectively, and a 28% increase in HDL cholesterol, with no significant change in the proportion of Lp A-I and Lp A-I/A-II particles. The abundance of cholesteryl ester transfer protein (CETP) mRNA in peripheral adipose tissue decreased with treatment in four of five patients studied; however, no change occurred in plasma CETP mass. Using an isotopic transfer assay, we demonstrated that both Lp A-I and Lp A-I/A-II participated in the CE transfer reaction, with no change after fenofibrate therapy. This finding suggests that the marked increase in HDL cholesterol during fenofibrate therapy is due to normalization of plasma TG and hence decreased opportunity for mass transfer of lipid between HDL and TG-rich proteins in vivo. In this population of hypertriglyceridemic subjects, CETP was distributed in both the Lp A-I and Lp A-I/A-II subfractions of HDL, with preferential association with the smaller Lp A-I poor. In contrast, in nine normal subjects studied, negligible amounts of CETP were associated with Lp A-I/A-II. Nonetheless, the Lp A-I/A-II fraction of HDL contributed significantly to total CE mass transfer in normolipidemic plasma. Lp A-I/A-II is an efficient donor for CE transfer to TG-rich lipoproteins, and its low affinity for CETP may in fact facilitate neutral lipid transfer either by a shuttle mechanism or by formation of a ternary complex.

Adult↗
PubMed1979

Simulated hyperglycemic hyperosmolar syndrome. Impaired insulin and epinephrine effects upon lipolysis in the isolated rat fat cell.

These investigations were designed to evaluate the effect of excess glucose and sodium chloride on lipolysis in the isolated adipocyte under normal and modelled pathological conditions simulating the hyperglycemic hyperosmolar syndrome. Isolated rat fat cells were incubated in the presence of various combinations of sodium chloride, glucose, epinephrine, and insulin. Lipolysis was measured as glycerol and free fatty acid release, and total medium osmolarity as milliosmoles per liter by freezing point depression. Basal lipolysis was unaffected by changes in osmolarity with sodium chloride, but glucose and glucose plus sodium chloride increased basal glycerol release. Increasing osmolarity with sodium chloride diminished the lipolytic response to epinephrine. Increasing osmolarity with glucose augmented the lipolytic response to epinephrine up to a total medium osmolarity of 550 mosmol. Higher osmolarities produced with glucose suppressed the epinephrine-induced lipolytic response.When the hyperglycemic hyperosmolar syndrome was simulated with 100 mM glucose and 50 mM sodium chloride (total osmolarity = 460 mosmol) the epinephrine-stimulated lipolysis dose-response curve in the isolated fat cell was shifted to the right. Furthermore, in the presence of 100 mM glucose + 50 mM sodium chloride, physiological concentrations of insulin were less effective in opposing epinephrine-stimulated lipolysis. In the presence of 50 mM glucose and 25 mM sodium chloride (total osmolarity = 370 mosmol) epinephrine-stimulated lipolysis measured as free fatty acid release was decreased by 50%. Under conditions simulating the hyperglycemic hyperosmolar syndrome in the isolated rat adipocyte, altered lipolysis reflects impaired effectiveness of both insulin and epinephrine as antilipolytic and lipolytic hormones, respectively. Furthermore, the attenuated response to both hormones appears to be primarily a function of extracellular solute composition. The lack of ketosis is the result of diminished release of free fatty acids from peripheral adipose cells.

Adipose Tissue↗
PubMed2001

[Monoaminergic anorectic agents].

Catecholamine, dopamine, serotonine (5HT) and neuronal histamine are anorectic monoamines and act as anorectic neurotransmitters. The anorectic agents as modulators of these monoamines inhibit appetite by activating release together with suppressing reuptake of those monoamines. The anorectic agents were classified in clinical use into either alpha 1, beta-adrenergic receptor agonists or 5HT-receptor agonist. Dexfenfluramine, a 5HT-receptor agonist, was inhibited in clinical use because of its cardiac complications including pulmonary hypertension and valvelar disease. Mazindol is an adrenergic agonist and the solitary anti-obesity drug used clinically in Japan. Sibutramine shows the effects of both beta-adrenergic and serotonergic receptor agonists. Sibutramine induces not only appetite suppression but also acceleration of peripheral energy expenditure. No histaminergic anorectics have been employed in the clinical situation to date. L-Histizine, precursor amino acid of endogenous neuronal histamine, is useful for suppression of food intake, lipolytic acceleration of peripheral adipose tissues and enhanced energy expenditure in both animals and humans. L-Histizine thus inspires development of more effective and safer anorectics that can be used without suffering from the rebound phenomenon of body weight.

Adrenergic Agents↗
PubMed2001

[Leptin-induced regulation of fat metabolism and its accumulation].

Recent findings have shown that supplementation of leptin decreases body weight in leptin-deficient ob/ob mice through its suppressive effect on food intake and accelerating effect on energy expenditure, particularly on peripheral fat lipolysis. When endogenously hyperleptinemic obese rats were further induced to be hyperleptinemic exogeously using adenovirus vector, their body fat mass was reduced but not food intake. These findings implicate a direct lipolytic action of leptin on peripheral adipose tissues in obese rats because leptin transport capacity across the blood-brain barrier is almost saturated by the relative hyperleptinemia. Recovery from excessive body fat accumulation after adenovirus-induced hyperleptinemia is much slower than that after caloric restriction because there may be difference between those treatments in decreased lipogenic enzymes activities and/or increased activities of fatty acid oxidative enzymes and thermogenic uncoupling proteins. The fat melting effects of leptin may show its crucial pharmacologic potencies to design therapeutic strategies against morbid obesity. The studies on leptin provide a better understanding for creative approaches to anti-obesity drug that are efficient for reducing body fat mass without harmful side-effects.

Animals↗
PubMed2005

Pharmacotherapy for obesity.

Pharmacotherapy for the management of obesity is primarily aimed at weight loss, weight loss maintenance and risk reduction, and has included thyroid hormone, amphetamines, phentermine, amfepramone (diethylpropion), phenylpropanolamine, mazindol, fenfluramines and, more recently, sibutramine and orlistat. These agents decrease appetite, reduce absorption of fat or increase energy expenditure. Primary endpoints used to evaluate anti-obesity drugs most frequently include mean weight loss, percentage weight loss and proportion of patients losing >or=5% and >or=10% of initial bodyweight. Secondary endpoints may include reduction in body fat, risk factors for cardiovascular disease and the incidences of diseases such as diabetes mellitus. Most pharmacotherapies have demonstrated significantly greater weight loss in patients on active treatment than those receiving placebo in short-term ( or=10% loss of initial bodyweight in 46% of patients. For patients taking orlistat, weight loss was 2.2 kg greater than those on placebo at 4 years (p<0.001), with significantly more patients achieving >or=10% loss of initial bodyweight (26.2% and 15.6%, respectively; p<0.001). Other drugs that have been evaluated for weight loss include ephedrine, the antidepressants fluoxetine and bupropion, and the antiepileptics topiramate and zonisamide. Two clinical trials with fluoxetine both reported no significant difference in weight loss compared with placebo at 52 weeks. Clinical trials evaluating ephedrine, bupropion, topiramate and zonisamide have demonstrated significantly greater weight loss than placebo but have been limited to 16-26 weeks' treatment. A major obstacle to the evaluation of the clinical trials is the potential bias resulting from low study completion rates. Completion rates varied from 52.8% of phentermine recipients in a 9-month study, to 40% of fenfluramine recipients in a 24-week comparative study with phentermine and 18% of amfepramone recipients in a 24-week study. One-year completion rates range from 51% to 73% for sibutramine and from 66% to 85% for orlistat. Other potential sources of bias include run-in periods and subsequent patient selection based on compliance or initial weight loss. Several potential new therapies targeting weight loss and obesity through the CNS pathways or peripheral adiposity signals are in early phase clinical trials. Over the next decade the drug treatment of obesity is likely to change significantly because of the availability of new pharmacotherapies to regulate eating behaviours, nutrient partitioning and/or energy expenditure.

Anti-Obesity Agents↗
PubMed1988

Strain differences in the dose-response curves of adrenalectomized, starved-refed rats to dehydroepiandrosterone (DHEA).

The effects of adrenalectomy and dehydroepiandrosterone (DHEA) doses (0, 15, 30, 60, 120 and 240 mg/kg/day ip) on hepatic enzyme activity and lipid content and on the amount of epididymal fat pad lipid were studied in starved-refed BHE and Sprague-Dawley rats. BHE rats had significantly greater relative liver size, glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme (ME) activities, and percentage liver lipid but less epididymal fat pad lipid than Sprague-Dawley rats. Adrenalectomized (ADX) rats consumed significantly less food, gained less weight per day, and had less lipid in their livers and fat pads than intact rats. As the level of DHEA increased from 0 to 240 mg/kg/day there was a significant linear decrease in average daily weight gain, food intake, G6PD activity, and percentage liver lipid. At the 15 mg/kg/day dose, G6PD activity was significantly reduced without reductions in the other parameters measured. At the 120 mg/kg/day dose, however, weight gain, food intake, G6PD activity, and percentage liver lipid were significantly lower than that of the controls. At this dose DHEA treatment reduced food intake by 17% whereas it diminished average daily weight gain and G6PD activity by 30 and 56%, respectively. The 240 mg/kg/day dose of DHEA significantly reduced food intake, weight gain, liver lipid, G6PD activity, and ME activity. Intact and ADX BHE rats reduced their G6PD activity and liver lipid more rapidly than Sprague-Dawley rats as the level of DHEA administered increased. ADX Sprague-Dawley rats receiving DHEA had greater liver lipid content and enzyme activity than their intact counterparts whereas the reverse situation was true in BHE rats. These data indicate that the effect of DHEA on body weight gain, food intake, and hepatic and peripheral adiposity are dependent on the strain of rat, the adrenal status, and the DHEA dose.

Adipose Tissue↗