Biomedical subjects

Ronald J Jandacek

Publications and source records attributed to Ronald J Jandacek.

10 recordsLinked to original sources

PubMed2006

The regulation of alcohol intake by melanin-concentrating hormone in rats.

Given into the brain, melanin-concentrating hormone (MCH) increases alcohol consumption, but the mechanism and physiological relevance of this effect are unclear. We hypothesized that endogenous MCH will enhance alcohol drinking and that MCH increases alcohol's reinforcing properties. An MCH receptor 1 (MCHR1) antagonist, or saline was administered centrally alone, or preceding MCH or saline to rats trained to drink 10% alcohol using sucrose fading. Blocking MCHR1 neither reduced alcohol intake (saline=0.4+/-0.1 g, 30 microg MCHR1 antagonist=0.4+/-0.1 g/kg alcohol), nor attenuated MCH-induced alcohol drinking (MCHR1 antagonist/saline=0.7+/-0.1 g/kg, MCHR1 antagonist/MCH=0.9+/-0.1 g/kg alcohol). Another cohort of rats was trained to lever press for alcohol on a progressive ratio schedule. MCH or saline was administered centrally and lever presses were measured. MCH had no effect prior to the break point, but increased total responding during the session (saline=87.2+/-32.0, MCH=315.4+/-61.0 presses). In conclusion, these data suggest that MCH augments alcohol drinking partly by enhancing the drug's reinforcing value. Further, endogenous MCH does not seem to regulate alcohol drinking, however because the antagonist failed to attenuate MCH-induced alcohol intake this conclusion is tentative.

Alcohol Drinking↗

PubMed2006

CD36 is important for chylomicron formation and secretion and may mediate cholesterol uptake in the proximal intestine.

BACKGROUND & AIMS: Studies are aimed to determine the role of CD36 in intestinal lipid absorption. METHODS: Knock-out (KO) and wild-type (WT) lymph fistula mice were used to study fatty acids (FA) and cholesterol uptake, and chylomicron formation and secretion. Uptake of FA and cholesterol was studied by using sucrose polybehenate and fecal dual isotope methods, respectively. RESULTS: The CD36 KO exhibited significant accumulation of dietary cholesterol in the intestinal lumen at the end of 6-hour lipid infusion and significant reduction of dietary cholesterol transport into the lymph. Fecal dual isotope studies, however, did not show any significant difference in cholesterol uptake, suggesting that given sufficient time, the KO intestine could compensate for the reduced cholesterol uptake observed in the acute lymph fistula studies. Recovery of dietary FA in the intestinal lumen was comparable between WT and KO, consistent with the sucrose polybehenate study. However, the KO mice accumulated more, albeit not significantly, dietary triacylglycerols in the intestine, followed by a significant reduction in lymphatic transport. The ratio of intestinal dietary triacylglycerols to FA was not higher in WT than KO, arguing against impaired lipid esterification. It is rather a deficiency in the formation and secretion of chylomicrons, as supported by the significantly less apolipoprotein B-48 and the smaller, albeit not significantly, lipoprotein particles secreted into the lymph of the KO. CONCLUSIONS: CD36 may play an important role in chylomicron formation and secretion and may also facilitate cholesterol uptake in the proximal intestine.

Animals↗

PubMed2005

Treatment with a dietary fat substitute decreased Arochlor 1254 contamination in an obese diabetic male.

A case manifesting symptoms due to organochlorine toxicity was treated with the fat substitute olestra in his diet. Before treatment, the patient was obese, with severe type 2 diabetes mellitus and mixed hyperlipidemia, chloracne, frequent headaches, and numbness and paraesthesias of his trunk and lower limbs. Earlier attempts at weight loss had been unsuccessful due to worsening of his symptoms. After inclusion of olestra in his diet for 2 years, weight loss was successful without aggravation of his symptoms, and the patient reverted to normoglycemia and normolipidemia. Olestra may have assisted weight loss and amelioration of his diabetes by increasing fecal elimination of organochlorines, rather than by preventing the partitioning of these pollutants into tissues, where they have been reported to exert antimetabolic effects on substrate oxidation.

Adipose Tissue↗

PubMed2005

APD-356 (Arena).

Arena is developing APD-356, the lead in a series of orally active, small-molecule 5-hydroxytryptamine 2C agonists for the potential treatment of obesity and diabetes. A phase IIb trial was initiated in June 2005, and preliminary results were expected at the end of 2005.

Animals↗

PubMed2004

Effects of yo-yo diet, caloric restriction, and olestra on tissue distribution of hexachlorobenzene.

Chlorinated hydrocarbons are lipophilic, toxic, and persistent in the environment and animal tissues. They enter the body in food and are stored in adipose tissue. Loss of body fat through caloric restriction mobilizes stored lipophilic xenobiotics and results in distribution to other tissues. We have studied the reversibility of this process in mice that followed a regimen of body weight cycling. Weight gain was followed by weight loss, a second gain, and a second loss ("yo-yo diet regimen"). We measured the distribution of orally gavaged [14C]hexachlorobenzene, which is sparingly metabolized. We found that weight cycling has different effects in different organs. Continued weight loss resulted in a threefold increase of 14C amount and concentration in the brain. After weight regain, 14C in the brain decreased but then increased again after a second weight loss. Weight loss resulted in an increase in the concentration of 14C in adipose tissue without changing the total amount in that tissue. Weight loss and regain resulted in an increase of 14C in the liver, which reflected an increase of fat in the liver. The regimen of weight gain and loss was repeated in mice gavaged with [14C]hexachlorobenzene, with one group receiving the nonabsorbable fat olestra in the diet. Combined dietary olestra and caloric restriction caused a 30-fold increase in the rate of excretion of 14C relative to an ad libitum diet or a reduced caloric diet alone. Distribution of 14C into the brain resulting from the restricted diet was reduced by 50% by dietary olestra.

Adipose Tissue↗

PubMed2004

Pharmaceutical approaches to the treatment of obesity.

The recent increase in pharmaceutical companies' efforts toward the treatment of obesity reflects recognition of the related health risks, the growth of knowledge about mechanisms that control energy balance, and the potential market for new compounds. The current patent literature gives a picture of the targets that are available for pharmaceutical intervention; these include signals of satiety and signals related to fat storage that act in the hypothalamus. The regulation of energy use and storage in adipocytes and the reduction of intestinal absorption of energy are also pharmaceutical focus areas. The multiplicity of targets illustrates not only the many potential approaches to the treatment of obesity but also the complexity and redundancy of the processes that regulate energy storage in the body.

Adipose Tissue↗

PubMed2004

Weight loss through ileal transposition is accompanied by increased ileal hormone secretion and synthesis in rats.

Bariatric surgeries, such as gastric bypass, result in dramatic and sustained weight loss that is usually attributed to a combination of gastric volume restriction and intestinal malabsorption. However, studies parceling out the contribution of enhanced intestinal stimulation in the absence of these two mechanisms have received little attention. Previous studies have demonstrated that patients who received intestinal bypass or Roux-en-Y surgery have increased release of gastrointestinal hormones. One possible mechanism for this increase is the rapid transit of nutrients into the intestine after eating. To determine whether there is increased secretion of anorectic peptides produced in the distal small intestine when this portion of the gut is given greater exposure to nutrients, we preformed ileal transpositions (IT) in rats. In this procedure, an isolated segment of ileum is transposed to the jejunum, resulting in an intestinal tract of normal length but an alteration in the normal distribution of endocrine cells along the gut. Rats with IT lost more weight (P < 0.05) and consumed less food (P < 0.05) than control rats with intestinal transections and reanastomosis without transposition. Weight loss in the IT rats was not due to malabsorption of nutrients. However, transposition of distal gut to a proximal location caused increased synthesis and release of the anorectic ileal hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY; P < 0.01). The association of weight loss with increased release of GLP-1 and PYY suggests that procedures that promote gastrointestinal endocrine function can reduce energy intake. These findings support the importance of evaluating the contribution of gastrointestinal hormones to the weight loss seen with bariatric surgery.

Adaptation, Physiological↗

PubMed2004

Identification and structural ramifications of a hinge domain in apolipoprotein A-I discoidal high-density lipoproteins of different size.

Apolipoprotein (apo) A-I is the major protein constituent of human high-density lipoprotein (HDL) and is likely responsible for many of its anti-atherogenic properties. Since distinct HDL size subspecies may play different roles in interactions critical for these properties, a key question concerns how apoA-I can adjust its conformation in response to changes in HDL particle size. A prominent hypothesis states that apoA-I contains a flexible "hinge domain" that can associate/dissociate from the lipoprotein as its diameter fluctuates. Although flexible domains clearly exist within HDL-bound apoA-I, this hypothesis has not been directly tested by assessing the ability of such domains to modulate their contacts with the lipid surface. In this work, discoidal HDL particles of different size were reconstituted with a series of human apoA-I mutants containing a single reporter tryptophan residue within each of its 22 amino acid amphipathic helical repeats. The particles also contained nitroxide spin labels, potent quenchers of tryptophan fluorescence, attached to the phospholipid acyl chains. We then measured the relative exposure of each tryptophan probe with increasing quencher concentrations. We found that, although there were modest structural changes across much of apoA-I, only helices 5, 6, and 7 exhibited significant differences in terms of exposure to lipid between large (96 A) and small (78 A) HDL particles. From these results, we present a model for a putative hinge domain in the context of recent "belt" and "hairpin" models of apoA-I structure in discoidal HDL particles.

Acrylamide↗

PubMed2004

Rapid clearance of hexachlorobenzene from chylomicrons.

Toxic organochlorines that are present in food are lipophilic and carried by chylomicrons. We have studied the clearance of an organochlorine, hexachlorobenzene, from chylomicrons. Chylomicrons were obtained from mesenteric lymph of rats that were intraduodenally given 14C-hexachlorobenzene and 3H-triolein. The labeled chylomicrons were injected intravenously into recipient rats, and the clearance of isotopes was followed. Surprisingly, the hexachlorobenzene disappeared from the plasma more rapidly than the triolein. This unexpected result raises questions about the manner in which hexachlorobenzene is delivered to tissues. The tissue distribution of the hexachlorobenzene is consistent with its rapid uptake.

Animals↗

PubMed2004

A novel, noninvasive method for the measurement of intestinal fat absorption.

BACKGROUND & AIMS: The goal of the study was to facilitate fat balance measurements with an appropriate intestinal marker for the transit of dietary fat and thereby eliminate the need for complete diet and fecal collections. METHODS: Dietary fat containing 5% sucrose polybehenate was fed in a semisynthetic diet to rats and mice. Fat absorption was calculated from the ratios of behenic acid to other fatty acids in diet and feces as analyzed by gas chromatography of fatty acid methyl esters. The method was validated by measuring absorption of well-absorbed (safflower oil) and poorly absorbed (olestra; calcium soaps) dietary fats. The animals were fed meals containing test fats for 2 or 3 days, and fecal samples were collected. Fecal samples of approximately 10 mg (single fecal pellet from mice) were assayed. RESULTS: The method yielded values that were consistent with complete absorption of safflower oil and the nonabsorbability of olestra and calcium soaps. The results were reproducible and consistent among individual fecal aliquots. The method was compared with traditional fat-balance methods in animals fed both high- and low-fat diets. CONCLUSIONS: Sucrose polybehenate is an appropriate marker that allows the rapid measurement of fat absorption by analyzing aliquots of <1% of total feces. The method is noninvasive, does not require isotope analyses, and can be carried out as part of an animal's normal feeding regimen. The method may be a facile technique to assess fat absorption measurements in humans.

Animals↗