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Biochemistry & Genetics

Numerous abnormalities of biochemistry and genetics have been found linked to obesity.  To the present, these have no impact on treatment.  In the future, they may lead to medications or individualized strategies to prevent and treat obesity.

Adiponectin: is secreted by fat cells and circulates in the blood. Plasma adiponectin concentration is reduced in obese animals and humans and in patients with type 2 diabetes mellitus. Adiponectin stimulates fatty acids oxidation, decreases plasma triglycerides, and improves glucose metabolism by increasing insulin sensitivity. In addition, adiponectin inhibits the inflammatory process and possibly atherogenesis by suppressing the migration of monocytes/macrophages and their transformation into foam cells. Plasma adiponectin is lower in patients with ischemic heart disease than in body mass index-matched healthy individuals. Hypoadiponectinemia may contribute to insulin resistance and accelerated atherogenesis associated with obesity. Med Sci Monit 2003 Feb;9(2):RA55-61.

Adiponectin Associated with Lower Endometrial and Breast Cancers: Adiponectin, a hormone with insulin-sensitizing properties, are decreased in conditions related to obesity and hyperinsulinemia, which are recognized risk factors for endometrial cancer. An Italian case(87)-control(132) study found an inverse association with endometrial cancer risk emerged for plasma adiponectin levels [odds ratio (OR), 0.42] when comparing the highest vs. the lowest tertiles. BMI and adiponectin showed independent effects on the risk of endometrial cancer according to a multiplicative model (OR, 6.45 in the highest level of BMI and in the lowest one of adiponectin). J Clin Endocrinol Metab. 2004 Mar;89(3):1160-3

Adiponectin Associated with Lower Breast Cancer in Post-Menopausal: In a Harvard case(167)-control(174) study, there was a fairly robust inverse association of adiponectin with breast cancer risk among postmenopausal women (odds ratio, 0.82), no such significant association between adiponectin and breast cancer was found among premenopausal women. J Clin Endocrinol Metab. 2004 Mar;89(3):1102-7

gAcrp30 Helps Mice: Human protein fragment, excreted by fat cells, helped mice on diet with unlimited sugar, butter, and oils burn fatty acids in muscles and lose weight. 30-40% of humans obese have low gAcrop30. Injectable only. French GENSET firm. Wash AP 2/17/01

Bulimia Causes Increased Hunger, CCK Involved: Self induced vomiting leads to slower gastric emptying. Small amounts of early gastric emptying during a meal release cholecystokinin CCK which goes to the brain and causes feelings of satiety. Bulimics develop slower emptying. Abstaining from bulimia for three months causes gastric emptying rate to return to normal and return of normal feelings of satiety.

C5L2 with ASP Important in Fat Stores: C5L2 protein is a cell surface receptor that binds acylation-stimulating protein (ASP), a protein known to affect fat production.  Obese have high levels of ASP. One potential key is to disrupt the ASP-C5L2 complex. Cianflone, Journal of Biological Chemistry 7/31/03 

ENPP1 Gene Abnormalities Linked to Obesity and Type 2 Diabetes: Faulty versions of the gene ENPP1 disrupt the way the body stores energy and handles sugar by blocking the hormone insulin. Children with faulty versions were obese at as young as five years old. Researchers compared the genes of 1,225 children who were grossly obese or overweight at ages 5-11 with 1,205 normal weight children they found an obvious pattern - many of the obese children possessed culprit versions of ENPP1. When they looked at the adults in the families, they found a similar link between the ENPP1 variants and obesity, as well as between the gene variants and early warning signs of diabetes. ENPP1 was also linked to full-blown type 2 diabetes in the adults. However, genetic testing is of no value at the present time.  Exercising, eliminating sugar and animal fats (beef, pork, and the skin of chickens) from the diet were mentioned as important strategies. Philippe Froguel et al. Institut Pasteur  Nature Genetics 7/17/05. Ed: Many other genetic abnormalities have been linked to diabetes. However, a truly healthy diet, exercise, certain vitamins and minerals, and medication when necessary are still the only means of prevention and treatment. For more, see Obesity and Diabetes.

Fatty Muscle Enzyme SCD-1 Plays Role in Obesity: Fat metabolism, fat storage, hunger, and obesity have a very complex system with many players. In a study comparing the severely obese and the lean, researchers found the fat-building enzyme stearoyl-CoA desaturase-1 (SCD-1) was three times more abundant in the muscle from the obese people.  SCD-1 slows down fat burning and promotes storage of fat droplets in the muscles.  When the researchers used genetic techniques to alter the cells of the lean individuals so they also had higher levels of the enzyme the cells began to store more fat. People may either inherit the SCD-1 genetic predisposition to obesity or develop it at some point in their life, possibly triggered by a poor diet. Exercise helps fight this type of obesity because regular physical activity encourages changes in the body to burn rather than lay down fat. Deborah Muoio et al. Cell Metabolism 10/12/05.

GAD2 Gene Variant Stimulates GABA and Hunger: 1200 French, half seriously overweight and half not studied. GAD2 gene speeds up production of GABA in the brain, which interacts with another molecule in the hypothalamus, causing a craving for food. Researchers discovered two different forms of the GAD2 gene. One is protective against obesity, while a mutated form increased the risk that someone would become severely overweight. Public Library of Science Biology 11/2/03, a journal available free online (www.plosbiology.org).

Gastric Inhibitory Polypeptide Helps Fat into Cells: Secreted by small intestine after food, est fatty. Binds cell-surface receptors on distant fat cells, signaling food intake. If sequence interrupted, mice burn excess fat rather than store it, become obesity resistant. Yamada, Kyoto U, Nature Medicine 6/20/02. GIP-receptor-deficient mice stay lean. Trying find chemical to block receptor as Rx for obesity.

Ghrelin Gets Hungry: Ghrelin is a 28 amino acid gut-brain peptide that is a powerful inducer of growth-hormone release. Released especially by stomach (gastrectomy cuts by 65%) and stimulates hunger. Inhibited by leptin, GH, high-fat diet. Rises during fasting and falls within an hour of eating. Basal hypothalamus has selectively permeable blood-brain barrier. In rats ghrelin can lead to obesity. Levels are decreased in average obese person. Lancet 4/20/02

Ghrelin Hunger Hormone: Journal of Clinical Endocrinology & Metabolism study from England shows ghrelin increases food consumption 28% vs. placebo. Similar effect in mice. 3/2002; Markedly decreased after gastric bypass vs. increased in dieters. NEJM 5/23/02 David Cummings U Wash Seattle

Ghrelin Highest in Prader-Willi: Genetic constant hunger and severe obesity. David Cummings. Ghrelin 4.5 times normal and 2.5 times individuals with similar obesity. Endocrine Society Meeting 6/19/02

GNB3 825T Obesity Gene: This one manufactures G proteins, substances that carry messages from the surface of cells into their centers. One common variety of this gene is called the GNB3 825T allele. The researchers found that people who inherit two copies of this particular gene variant are three times more likely to be obese than are those who get one copy or two completely different variations of the gene. AP New Orleans 11/14/00. 60% blacks, 20% Asians, 10% Europeans have two copies of the unfavorable type. In Germans, 23% obese vs. 8% normals with two copies. The impact can be offset by 30 min exercise/week.

Malonyl-CoA Shortage Helps Drive Hunger: Appetite is immediately and inversely tied to amounts of a chemical called malonyl-CoA. In hungry mice, malonyl-CoA was almost undetectable in the brain. Once fasting mice were given food, however, amounts of the chemical increased to high levels within two hours. Johns Hopkins, Proceedings of the National Academy of Sciences 12/03

Leptin Levels Risk Factor: 30% increase in blood leptin linked to 25% increase in heart attacks. Leptin reflects level of obesity and lower by exercise. C-reactive protein also increases with leptin levels. Circulation 12/18/01.

Leptin Up in NIDDM: Serum leptin increased with increase in body mass index and waist hip ratio was strongly related with insulin resistance in NIDDM. J Coll Physicians Surg Pak 2003 Mar;13(3):130-4

Leptin: Abnormal Leptin Causes Obesity in Turkish Family: While most obese have excess leptin, three members of a Turkish family had very little due to a SNP in the leptin gene. Leptin injections resulted in 100# wt loss on average and caused increased sexual maturity and improved periods. Lucinio, UCLA, Rueters Washington, 7/25/02

Melanocyte Stimulating Hormone Releases Fat from Stores: University of Denver and the Oklahoma Medical Research Foundation found that mice missing the pro-opio melanocortin (POMC) gene  had no MSH in their bloodstream and became obese because they stored all the fat they ate without metabolizing any of it. They reduced their weight by adding MSH back into the peripheral circulation. There are MSH receptors in essentially all peripheral tissues. MSH causes the adipocytes, or fat cells, to release free fatty acids, while other cells are stimulated to remove them from the bloodstream and burn them. MSH has the highest activity when you have the highest level of excess weight. As the animal approaches normal weight, the effect plateaus out. Science News 5/13/04

Orexin Thought to Play a Role in Obesity: Orexin stimulates the human adrenal gland to produce cortisol which in turn can cause obesity. Orexin activity can be found in several areas of the male genitals with receptors in the testis and penis where it has a more positive affects on testicular cells responsible for making testosterone, the primary male sex hormone, and in tubules that are responsible for producing sperm. Receptors are also present in the epididymis, implicating orexins in events that include transport and storage of sperm cells. Orexin may help control penile function including the maintenance of penile erection. Harpal Randeva et al, Univ Warwick, J Clin Endocrinology and Metabolism 4/6/04

PPAR-delta Drug May Help Obesity: A drug being developed by GlaxoSmithKline to fight obesity activates a protein in the body called PPAR-delta that increases the rate at which fat is burned. It may reduce obesity as well as reducing the risk of stroke, diabetes and coronary disease. The tablet has been tested on mice and increased their athleticism considerably. Daily Mirror 1/10/05

PPARd Receptor Heat Generator Prevents Obesity: April 18, 03 Cell, Ronald M. Evans, Salk Institute. Stimulating the peroxisome proliferators-activated receptor depleted fat deposits in mice, while mice deficient in PPARd were prone to obesity. PPARd regulates the rate by which fat is burned to produce heat or is used to maintain normal cell functions. The process of uncoupling energy from work production to heat generation, known as adaptive thermogenesis, is generally regarded as a physiological defense against obesity. Mice with an activated PPARd gene weighed about 20 percent less, even though same food at the same rate. Once the mice were a year old, the difference in weight widened, to 35 percent less. Mice that had the active PPARd gene did not show significant weight gain over a month's time, despite having a high-calorie, high-fat diet. Mice without the active gene, however, became obese. Short-term treatment of the obese mice with a molecule that activated PPARd caused a dramatic reduction in fat in their tissues.

PYY3-36 Hormone Reduces Intake: Nature 8/9/02 article about hormone (Peripheral YY) secreted by intestinal lining cells increases with intake and remains high after meals. Injections given to 20 normal adults reduced single meal intake by 33%. Mouse research documents hormone works on hypothalamus. 24 hour consumption in humans was reduced by 20%. Expert Opin Investig Drugs. 2004 Mar;13(3):285-

Resistin Causes DM Obesity: Produced by fat cells, the hormone resistin causes the cells to resist insulin. Obesity is a big risk factor for Type II diabetes. TZD drugs help body use insulin more effectively. The drug affects genes for resistin. Nature 1/18/01.

Neuropharmalogy 5-HT2C, Beta-3, Leptin, Neuropeptide Y, Galanin, Histamine-1 Receptor: 5-HT2C Receptors key role in appetitie. Mice lacking these are obese. Activating these in mice decr eating. Fenfluramine releases serotonin at all 5-HT receptors. SRIs and SNRIs (serotonin plus norepinephrine reuptake inhibitors) can reduce appetite with fluoxetine possibly the most and a specific indication for bulimia. It is the only with direct 5-HT2C agonist activity. Sibutramine (Meridia) works by 5-HT and NE reuptake blackade like high dose venlafaxine. Also, 3 types Beta receptors: Beta-1 a cardiac receptor, Beta-2 in lungs and targeted by bronchodilators and also in uterus and skeletal muscles. Beta-3 in adipose tissue regulates nrg metab and thermogenesis, esp in resonse to NE. Genetic variant of beta-3 rale in morbid obesity and NIDDM, e.g. in Pima Indians. Also found incr in obese in Japan, and in 25% black and 10% Europeans Sibutrmine incr NE at beta-3. Histamine-1 Repectors antagonists sedating and incr appetite. Antidepr and antipsychotics blocking it cause wt gain. 3 peptides involved: galanin, neuropeptide Y and leptin. Leptin a interleukin 6 cytokine. Regulates insulin secretion and nrg metab. Humans without leptin severe obesity. However, levels incr in obese and decr in anorexia. Y and galanin incr in obese. Thus obesity maybe leptin resistant. Stahl, J Clin Psychiatry 9/98. 59:447-8

Sleep Related Eating Disorder: Common pattern with 83% female. Begins in adolescence and is chronic, usually nightly up to 6 times following a period of sleep with binging and half-awake. Half with sleepwalking. J Clin Psychiatry 1/98.

Tumor Necrosis Factors Involved: Immunoendocrine leptin, TNF-alpha, sTNF-R p55, and sTNF-R p75 all increased with mirtazazepine in unison with weight gain although leptin was slowest to respond. Venlafaxine did not cause any change.Max Planck, Munich, Body Weight, the Tumor Necrosis Factor System, and Leptin Production during Treatment with Mirtazapine or Venlafaxine. Kraus T, Haack M, Schuld A, Hinze-Selch D, Koethe D, Pollmacher T. Pharmacopsychiatry 2002 Nov;35(6):220-5

Viral Induced Obesity: Adenovirus-36 injected in chickens and mice at U Wisc and twice as much fat. 20-30% overweight humans infected with Ad-36 vs 5% of thin. (Internal J Obesity 8/00). Another study of human adenovirus-37 found it, but not Ad-2 or Ad-31, caused young chicks to gain weight in internal organs. Atkinson, U Wisconsin Sci News 3/16/02

Thomas E. Radecki, M.D., J.D.

modern-psychiatry.com

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