Happy pre-Thanksgiving!
On that note, I thought I’d catch up on weight loss abstracts.
1. New Phen-fens without the side effects look good, and they may also be useful in treating diabetes. They may have an “anxiety” type side effect initially.
2. Leptin plus a satiety protein (Amylin’s pramlintide) makes 200+ pound people lose about 25 pounds in 24 weeks. And surprise! Leptin is the thing that regulates satiety/hunger signals right there in the brain.
(I put a song about losing weight in the last post, just to celebrate, (Last post)).
Lots more after the jump, full abstracts, history of Phen-fen and updates, picture of hippos, you get your money’s worth after the jump (of course it’s free. . .)
I’ve been around anti-obesity meds on and off since the mid-1990′s. Nearly every world-class endocrinologist who powerpointed through the conference rooms said the same thing: where and how much fat is on your body depends on your parents. In twin studies, the correlation was higher than that for alcoholism or schizophrenia. If your parents were giraffes, you’ll be a giraffe. If they were hippos, you’ll be a hippo. If they were Asian, you’ll be Asian. If they were Pima Indian, you’ll be Pima Indian.
There seems to be a public bias against pathologizing obesity (similar to alcoholism). While lifestyle can make you fat or slim, clearly it isn’t working in the U.S. There is an anti-fast food backlash, particularly against french fries, it seems. The Food and Drug Administration has an obesity working group — with the predominant theme of nutrition –” Count Calories.” Again, a volitional approach. I supposed it worked for smoking. But french fries aren’t cigarettes.
So, in fact, take french fries — the FDA is at cross purposes with the USDA, who wants people to eat more potatoes:
The growth of the U.S. food service sector has driven the shift toward frozen potato use. In 2005, U.S. per capita use of frozen potatoes was 56 pounds per year, compared with 45 pounds for fresh potatoes, 17 pounds for potato chips, and 16 pounds for dehydrated products. Average per capita value, including net imports, amounted to $8.10 per year, of which half ($4) was for processed potatoes
Be that as it may, I checked in on recent reports in the anti-obesity med field. Abstracts from PubMed are reprinted after the jump.
The new “sons of Phen -Fen”. Here’s the theory: make Phen-Fen safe and it will sell itself. You already know the sales numbers.
Seems like a good idea to me.
In 1996, an estimated 18 million prescriptions were written for this combo, and at its peak in 1997, an estimated 2.5MM people in the US were on anti-obesity meds.
Let’s do some math:
2.5 million people x $100 a month profit for a drug co. x 12 mo. = $3B. Easy.
Most of the 1997 prescriptions were the “phen-fen” combo. Because the drug combo caused heart problems, it was withdrawn for anti-obesity use in 1997 in the US (here’s the FDA website for the full background).
A huge class action ensued against Wyeth (who bought American Home Products), the main manufacturer, although others were also sued. Wyeth settled for billions. Some say to pay for the settlement Wyeth sold Immunex (part of American Home Products) to Amgen.
To add to the drama, some of the class action lawyers allegedly kept the settlement money that was supposed to go to the injured patients — and are now in jail awaiting a criminal trial.
Recent reports somewhat indicate that the heart problems were (a) more or less as widespread as originally thought, but (b) probably reversible — so the initial problems cleared up.
So, why is it a good idea to try Phen-fen again?
Because this time you can make the drug more specific to the brain, and avoid the heart.
The “sons of phen-fen”are selective for a receptor subtype — 5-HT2C (as distinguished from the “A” or “B” subtype.) The “C” subtype is found in the brain — not in the heart or anywhere else. (The 5-HT2A and 5-HT2B sub types are found in other parts of the body, including the heart — which was Phen-fen’s problem).
Receptor subtype 5-HT2C agonists have been looked at in preclinical trials, and at least one, lorcaserin HCL is in the clinic .
(This is strange: a Chinese manufacturing company sells lorcaserin : “pharma-chemical.com ::Tel:+86-571-85054016 ,FAX:+86-571-85054082
Address:3F Hangzhou Yiyao Building,No.439 Zhong Shan North Rd.,Hangzhou China”)
So what’s the latest?
Really good news:
This specific 5-HT2C receptor also can improve diabetes by regulating glucose metabolism control in the brain.
Also, an animal study showed that these drugs can reduce cocaine dependence (see the abstracts after the jump).
Probably not surprisingly, the Phen-fenish meds can make you more anxious, at least temporarily.
There is also a rare genetic component: Some people have “edited” 5-HT2C receptor protein, and a psychiatric comorbidity. There may be unwarranted psychiatric effects if people who have both (such as biopolar as well as an “edited” 5-HT2C RNA).
With the anti-cannabinoids (Acomplia or Zimulti), apparently depression and suicide are issues (somehow, if you block the “marijuana makes me happy and hungry” receptor, depression doesn’t surprise me).
So far, with lorcaserin, the reports indicate it is Phen-fen without the side effects. The company sponsor, Arena Pharmaceuticals, is still conducting the clinical trials.
Conducting a clinical trial with the endpoint “weight loss” is tough. The FDA told the lorcaserin folks to slow down, get more data, find unambiguous results.
Then there’s leptin. I lurve leptin.
This has had more money and more science thrown at it than any other protein I can think of. Everyone knows that this stuff is important to fat somehow, but, turning it into a weight loss med has been a long road. Leptin isn’t a pill, it’s a protein so it has to be injected (unlike the 5-HT2C agonists). Previous clinical trials with leptin alone did not demonstrate any “wow” result, although in the test tube and in animal models, clearly there is a fat-regulating effect. (I briefly wrote about leptin and the smell of food as part of Seven Deadly Sins month).
I remember hearing about a group of people of a particular nationality, living in the UK, who were producing children with a homogous recessive trait — lack of a functional leptin gene.
These children were tragic — over 200 pounds by first grade, failing to mature at puberty, and very likely on their way to an early death. To me, this really was the first time I understood the prohibitions against marrying a close relative, and the potential tragic outcomes.
In the late ’90′s, these children were treated with leptin, and, for all intents and purposes, cured. Full stop. Replacement protein therapy.Leptin is made in fat cells. Originally, because leptin is a protein, it was thought to work on your peripheral fat directly, thereby somehow sending off a smaller messenger molecule to the brain — a molecule small enough to get past the blood brain barrier. People said, “Leptin will never be a drug because how will you get it into the brain?”
Well, at least it gets in the brain.
Whether or not it is ever a drug is a different question.
There are three new leptin reports (at least three. . . but here are three that caught my eye):
- Leptin plus an extra hormone looks good in the clinic for weight loss;
- Leptin in the brain regulates appetite; and
- Leptin in the brain is correlated with satiety, lack of leptin is correlated with hunger.
I wonder if we’ll look back at these studies and think this was the golden era of leptin research. Finally everyone is coming together — the clinicians, the cellular and molecular people and the brain scanners.
Basically, it looks like leptin acts as a graphic equalizer in the brain: signalling to turn up the satiety signals or turn down the hunger signals.
Amylin reported a new study that leptin combination treatment demonstrates 12.7 percent weight loss in a 24-week clinical obesity study. The other drug in the trial was Symlin — a protein that signals “oofta, I’m full.” Symlin stimulates insulin secretion, slows emptying of the stomach and inhibits production of glucose by the liver. It also appears to suppress appetite and helps weight loss (although I had heard rumors — unsubstantiated and now apparently totally wrong rumors) that the weight loss was because everyone was nauseous.
The Proceedings of the National Academy of Science has a report that leptin works in the brain. Leptin regulates fatty acid metabolism in the brain and that, indirectly, regulates appetite. Wow.
Another PNAS paper shows via brain scans that leptin quenches the desire for food. Three leptin-deficient adults, from the same family, were shown photos of fatty food (or lean food) while having their brains scanned. They were scanned before leptin treatment and then after two years of leptin treatment. Leptin replacement reduced activation in brain areas linked to hunger (insula, parietal and temporal cortex) but increased activation in regions associated with inhibition and satiety (prefrontal cortex). At least for fatty food. Clearly, then, there is a biochemical process going on, and more than just “counting calories.”
A similar study was conducted in England, and recently published. (This is confusing because on the UCLA PNAS paper, one of the main researchers is Dr. London. Dr. London is in Los Angeles, however, not England. )
Who knew? I suppose Symlin, which has something to do with satiety, sends signals to the brain, which then signals leptin to bind to leptin receptors in the hypothalamus. Once the receptors are bound, you are not interested in hunting down food — so those parts of your brain don’t light up — but you merely observe food, so the parts of your brain that do trigonometry are active.
There. Fini. Abstracts below the jump.
Cell Metab. 2007 Nov;6(5):398-405
Serotonin 2C Receptor Agonists Improve Type 2 Diabetes via Melanocortin-4 Receptor Signaling Pathways.
Zhou L, Sutton GM, Rochford JJ, Semple RK, Lam DD, Oksanen LJ, Thornton-Jones ZD, Clifton PG, Yueh CY, Evans ML, McCrimmon RJ, Elmquist JK, Butler AA, Heisler LK.
Department of Clinical Biochemistry, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 2QQ, UK; Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
The burden of type 2 diabetes and its associated premature morbidity and mortality is rapidly growing, and the need for novel efficacious treatments is pressing. We report here that serotonin 2C receptor (5-HT(2C)R) agonists, typically investigated for their anorectic properties, significantly improve glucose tolerance and reduce plasma insulin in murine models of obesity and type 2 diabetes. Importantly, 5-HT(2C)R agonist-induced improvements in glucose homeostasis occurred at concentrations of agonist that had no effect on ingestive behavior, energy expenditure, locomotor activity, body weight, or fat mass. We determined that this primary effect on glucose homeostasis requires downstream activation of melanocortin-4 receptors (MC4Rs), but not MC3Rs. These findings suggest that pharmacological targeting of 5-HT(2C)Rs may enhance glucose tolerance independently of alterations in body weight and that this may prove an effective and mechanistically novel strategy in the treatment of type 2 diabetes.
PMID: 17983585 [PubMed - in process]
Biol Psychiatry. 2007 Nov 15;62(10):1111-8. Epub 2007 May 23
Acute Selective Serotonin Reuptake Inhibitors Increase Conditioned Fear Expression: Blockade With a 5-HT(2C) Receptor Antagonist.
Burghardt NS, Bush DE, McEwen BS, Ledoux JE.
W.M. Keck Foundation Laboratory of Neurobiology, Center for Neural Science, New York University, New York, New York.
BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) effectively treat various anxiety disorders, although symptoms of anxiety are often exacerbated during early stages of treatment. We previously reported that acute treatment with the SSRI citalopram enhances the acquisition of auditory fear conditioning, which is consistent with the initial anxiogenic effects reported clinically. Here, we extend our findings by assessing the effects of acute SSRI treatment on the expression of previously acquired conditioned fear. METHODS: Rats underwent fear conditioning drug-free. Tone-evoked fear responses were tested after drug treatment the following day. This protocol more closely resembles the clinical setting than pre-conditioning treatment, because it evaluates effects of treatment on a pre-existing fear rather than on the formation of a new fear memory. RESULTS: A single pre-testing injection of the SSRIs citalopram or fluoxetine significantly increased fear expression. There was no effect of the antidepressant tianeptine or the norepinephrine reuptake inhibitor tomoxetine, indicating that this effect is specific to SSRIs. The SSRI-induced enhancement in fear expression was not blocked by tropisetron, a 5-HT(3) receptor antagonist, but was blocked by SB 242084, a specific 5-HT(2C) receptor antagonist. CONCLUSIONS: Enhanced activation of 5-HT(2C) receptors might be a mechanism for the anxiogenic effects of SSRIs observed initially during treatment.
PMID: 17524369 [PubMed - in process]
Behav Pharmacol. 2007 Dec;18(8):791-800
Stimulation of 5-HT2C receptors attenuates cue and cocaine-primed reinstatement of cocaine-seeking behavior in rats.
Department of Psychology, Arizona State University, Tempe, Arizona, USA.
The extinction/reinstatement model has been used in this study to examine the role of 5-HT2C receptors in cocaine-seeking behavior elicited by cocaine-associated cues and cocaine-priming injections. Rats that had been trained to press a lever for cocaine (0.75 mg/kg/0.1 ml, intravenously) paired with light and tone cues underwent daily extinction sessions, during which responding had no consequences. After responding diminished, rats were tested for reinstatement of responding by either response-contingent presentations of the cues or a cocaine-priming injection (10 mg/kg, intraperitoneal, i.p.), with and without pretreatment with the 5-HT2C/2B receptor agonist, MK 212 (0.0-1.0 mg/kg, i.p.). MK 212 attenuated cue and cocaine-primed reinstatement, as well as spontaneous and cocaine-induced locomotion at all doses tested. These effects were reversed by coadministration of the 5-HT2C-selective receptor antagonist, SB 242 084 (3.0 mg/kg, i.p.), suggesting they are 5-HT2C receptor-mediated. Although we cannot rule out the possibility that motor impairment might have been involved in the MK 212 effects on cocaine-seeking behavior, some aspects of the data favor the explanation that MK 212 decreases the motivational effects of cocaine and cocaine cues. The latter interpretation is consistent with a growing body of literature suggesting that 5-HT2C receptors play a role in motivated behaviors in general.
PMID: 17989517 [PubMed - in process]
Mol Psychiatry. 2007 Sep 11; [Epub ahead of print]
Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide
Dracheva S, Patel N, Woo DA, Marcus SM, Siever LJ, Haroutunian V.
[1] 1Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA [2] 2MIRECC, James J Peters Veterans Affairs Medical Center, Bronx, NY, USA.
Suicide is a major public health problem with approximately 1 million victims each year worldwide. Up to 90% of adults who commit suicide have at least one psychiatric diagnosis such as major depression, bipolar disorder (BPD), schizophrenia (SZ), substance abuse or dependence. A question that has remained unanswered is whether the biological substrates of suicide are distinct from those of the psychiatric disorders in which it occurs. The serotonin 2C receptor (5-HT(2C)R) has been implicated in depression and suicide. We, therefore, compared the frequencies of its mRNA editing variants in postmortem prefrontal cortical specimens from subjects who committed suicide or who died from other causes. All suicides occurred in the context of either SZ or BPD. The non-suicide cases included subjects with either SZ or BPD as well as subjects with no psychiatric diagnosis. We identified 5-HT(2C)R mRNA editing variations that were associated with suicide but not with the comorbid psychiatric diagnoses, and were not influenced by demographic characteristics (age and sex) and alcohol or drug use. These variations consisted of a significant increase in the pool of mRNA variants (ACD and ABCD) that encode one of the most prevalent and highly edited isoforms of 5-HT(2C)R, that is, VSV (Val156-Ser158-Val160). Because the VSV isoform of 5-HT(2C)R exhibits low functional activity, an increase in its expression frequency may significantly influence the serotonergic regulation of the brain. Thus, at least in patients with SZ or BPD, overexpression of the VSV isoform in the prefrontal cortex may represent an additional risk factor for suicidal behavior.Molecular Psychiatry advance online publication, 11 September 2007; doi:10.1038/sj.mp.4002081.
PMID: 17848916 [PubMed - as supplied by publisher]
Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17358-63. Epub 2007 Oct 23
From the Cover: Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake.
Gao S, Kinzig KP, Aja S, Scott KA, Keung W, Kelly S, Strynadka K, Chohnan S, Smith WW, Tamashiro KL, Ladenheim EE, Ronnett GV, Tu Y, Birnbaum MJ, Lopaschuk GD, Moran TH.
Departments of Biological Chemistry, Psychiatry and Behavioral Sciences, and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Hypothalamic fatty acid metabolism has recently been implicated in the controls of food intake and energy homeostasis. We report that intracerebroventricular (ICV) injection of leptin, concomitant with inhibiting AMP-activated kinase (AMPK), activates acetyl-CoA carboxylase (ACC), the key regulatory enzyme in fatty acid biosynthesis, in the arcuate nucleus (Arc) and paraventricular nucleus (PVN) in the hypothalamus. Arc overexpression of constitutively active AMPK prevents the Arc ACC activation in response to ICV leptin, supporting the hypothesis that AMPK lies upstream of ACC in leptin’s Arc intracellular signaling pathway. Inhibiting hypothalamic ACC with 5-tetradecyloxy-2-furoic acid, a specific ACC inhibitor, blocks leptin-mediated decreases in food intake, body weight, and mRNA level of the orexigenic neuropeptide NPY. These results show that hypothalamic ACC activation makes an important contribution to leptin’s anorectic effects. Furthermore, we find that ICV leptin up-regulates the level of malonyl-CoA (the intermediate of fatty acid biosynthesis) specifically in the Arc and increases the level of palmitoyl-CoA (a major product of fatty acid biosynthesis) specifically in the PVN. The rises of both levels are blocked by 5-tetradecyloxy-2-furoic acid along with the blockade of leptin-mediated hypophagia. These data suggest malonyl-CoA as a downstream mediator of ACC in leptin’s signaling pathway in the Arc and imply that palmitoyl-CoA, instead of malonyl-CoA, could be an effector in relaying ACC signaling in the PVN. Together, these findings highlight site-specific impacts of hypothalamic ACC activation in leptin’s anorectic signaling cascade.
PMID: 17956983 [PubMed - in process]
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18276-18279. Epub 2007 Nov 6.
From the Cover: Leptin replacement alters brain response to food cues in genetically leptin-deficient adults.
Baicy K, London ED, Monterosso J, Wong ML, Delibasi T, Sharma A, Licinio J.
Department of Psychiatry and Biobehavioral Sciences and Semel Institute, and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90024.
A missense mutation in the ob gene causes leptin deficiency and morbid obesity. Leptin replacement to three adults with this mutation normalized body weight and eating behavior. Because the neural circuits mediating these changes were unknown, we paired functional magnetic resonance imaging (fMRI) with presentation of food cues to these subjects. During viewing of food-related stimuli, leptin replacement reduced brain activation in regions linked to hunger (insula, parietal and temporal cortex) while enhancing activation in regions linked to inhibition and satiety (prefrontal cortex). Leptin appears to modulate feeding behavior through these circuits, suggesting therapeutic targets for human obesity.
PMID: 17986612 [PubMed - as supplied by publisher]
very interesting.
i’m adding in RSS Reader
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