What About Oxytocin?

It seemed that Childhood Obesity News‘ examination of currently available weight-loss drugs had come to an end, but no. As it turns out, another hormone might be in the running. This news was revealed at the latest annual meeting of the Endocrine Society. It comes from neuroendocrinologist and associate professor of medicine Elizabeth Lawson, and colleagues at Harvard Medical School.

They already knew that oxytocin improves the body’s sensitivity to insulin and somehow encourages the use of fat as fuel. Olga Khazan wrote for The Atlantic,

Lawson’s other studies have shown that oxytocin reduces activation in the hypothalamus, an area of the brain that controls hunger, and increases activation in areas of the brain associated with impulse control. To Lawson, the results together suggest that the hormone creates less of a need to eat, reduces the compulsion to eat for fun, and improves impulse control when it comes to actually reaching for that second slice of cake. Oxytocin, in other words, appears to make food seem less rewarding.

More recently, in a very small study involving 10 overweight and obese men, the subjects were shown pictures of high-calorie foods. Consequently, “the regions of the brain involved in eating for pleasure lit up.” This comes under the heading of over-activation, because being stimulated to eat when the body does not actually need nutrition serves no useful purpose, and leads to damaging behavior. However,

A dose of oxytocin, compared with a placebo, weakened the activity in those regions, and it also reduced the activity between them. Meanwhile, oxytocin didn’t have that effect when the men viewed images of low-calorie foods or household items.

Apparently, oxytocin enhances the sense of being satiated, or full, which obviously helps to prevent unnecessary eating. However, and this is a problem with many experiments, it is not yet clear whether the brain over-activation causes obesity, or whether obesity causes the over-activation. So plenty of work is yet to be done. The numbers need to be bigger, and at least half the subjects need to be women. And yet, in laboratory rodent tests, when it comes to central oxytocin pathway gene expression, sex doesn’t seem to make a difference.

Or maybe it does

Here is a weird little result suggesting that there are sex differences:

[Researchers] also found that men who had been given oxytocin, compared to men who received the placebo, expressed a stronger desire to date women who had previously been unfaithful. There was no equivalent effect of oxytocin on the female volunteers, but oxytocin did increase women’s interest in long-term relationships with faithful men.

In short, oxytocin didn’t simply turn men and women lovey-dovey; instead, it promoted the pre-existing sex differences in men’s and women’s preferences for faithful and unfaithful partners.

Research from Oslo University Hospital indicated hope for using oxytocin to regulate appetite in humans. They also found that it influences cognition and social behavior, including the processing of social cues. Proficiency in these areas could mitigate a person’s basic reasons for overeating in the first place.

One of the problems with research so far is the delivery system best practice. Although nasal spray is very effective in keeping test subjects from discriminating between an active dose and a placebo, the researchers really have no way of knowing how much of the substance gets through to the brain.

Another problem is that like many drugs, oxytocin seems to work differently on different people at different times and for different reasons. In other words, it’s that old spoiler again, multifactorialism.

For instance, human obesity has many causes, including psychological ones. The particular, individual cause could influence the outcome, a lot. As always, one question would be, “But is it safe for long-term use?” Since the body itself makes plenty of oxytocin, the answer would seem to be yes — but you never know.

(To be continued…)

Your responses and feedback are welcome!

Source: “The ‘Cuddle Hormone’ Might Help America Take On the Obesity Epidemic,” TheAtlantic.com, April 2019
Source: “Oxytocin: More Than Just a “Love Hormone,” PsychologyToday.com, 02/20/19
Source: “Oxytocin pathway gene networks in the human brain,” Nature.com, 02/08/19
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Myths to Forget

Not long ago, IFLScience.com published a list of “23 Facts You Learned About Healthy Eating As A Kid That Are No Longer True,” replete with plenty of source links for those who wish to know where the information came from. The top three are especially significant to the author, Hilary Brueck, so we too will start with those.

The first myth is that low-fat food products are inevitably better for the waistline than high-fat variants of the same food. Our bodies need fat for many purposes, and when we don’t get enough, we eat sugar and carbs, which are actively destructive. Whole milk is okay, too.

Childhood Obesity News has touched on this topic, which concerns one of the most far-reaching and harmful con games ever engineered by dishonest “authorities.” Another of the author’s top three myths is that urine should be clear with no yellow tinge, because if that’s going on, it means the person is over-hydrated.

Brueck also wants readers to know that “electrolytes and performance drinks don’t do anything special for your body,” information that might disappoint stockholders in the $12-billion-per-year energy beverage market. Here goes another cherished belief: that breakfast is the most important meal. The author says if you’re hungry eat; if not, don’t. However, it does seem to be true that for people who work out in the morning, empty-stomach activity burns as much as 20 percent more body fat.

It is hard to believe that anyone still thinks processed cereal is a great breakfast food, although apparently that belief is still common. Likewise, the idea that 100 percent real fruit juice is a good choice. Without the fiber that comes with whole fruit, the body doesn’t know what to do with the influx of sugar water. Here is a scary quotation:

Scientists recently looked at the health records of more than 13,400 US adults, and concluded that each additional 12-ounce serving of juice people drank per day was associated with a 24% higher risk of death.

This is a bit confusing, because in reality we all face a 100 percent risk of death, so let’s check the source. It goes back to a very recent Harvard study published in the Journal of the American Medical Association that compared fruit juices to sugar-sweetened beverages (SSBs), the more formal name for fizzy drinks or soda pop. It includes some very complicated findings regarding SSBs, natural juices, and all-cause mortality, and like most studies, a sentence that begins, “Clearly, more research is needed…” Also, people should be aware that diet soda is really no better that full-on soda, for one’s overall health.

“Snacking is healthy” is a myth, and so is “Fasting is bad for your health.” Intermittent fasting is the hot new concept, but at its most basic level, it simply means that people should let there be at least 12 consecutive hours out of 24 in which nothing is eaten. Say, from 7 PM to 7 AM. That doesn’t sound too shocking, does it?

Another myth is that most people do not consume enough protein. Actually, most Americans do, although they would be better off getting it from plants rather than meat. Brueck also breaks it to readers that carob is no healthier than chocolate; chocolate does not cause acne; most store-bought yogurt is crap; margarine kills; salt does not kill; coffee is okay; and egg consumption is not related to heart disease.

Your responses and feedback are welcome!

Source: “23 Facts You Learned About Healthy Eating As A Kid That Are No Longer True,” IFLScience.com, 06/21/19
Source: “Are Fruit Juices Just as Unhealthy as Sugar-Sweetened Beverages?,” JAMANetwork.com, 05/17/19
Photo on Visualhunt

Vitamin D for Weight Loss?

Parathyroid hormone is suspected of causing the body to hoard fat. We learn from Vitagene.com that “stored vitamin D tells the hypothalamus to decrease the output of parathyroid hormone.” Conversely, when incoming vitamin D is too low, that shortage is interpreted as a signal to store fat throughout the body, and especially around the waist area. Also, we are told that:

[…] a study in Nutrition Journal found that overweight and obese women who took 1,000 IU of Vitamin D every day for 12 weeks lost a measurable amount of fat mass independent of other bodily changes.

The nutrient also engages in molecular signaling to inhibit inflammatory substances from adhering to cell walls and causing stress and inflammation. In addition, the body’s organs also have receptors that turn vitamin D into the activated or hormonal form known as calcitriol. This hormonal version of vitamin D helps repair cells, fights oxidation, and may even increase longevity.

There is good news for people with type 2 diabetes, or who are at risk for it, because D can increase insulin secretion. It can also increase the release of leptin, the hormone that says “I’m full.” For patients who undergo bariatric surgery, vitamin D supplementation is strongly advised.

Vitamin D helps the body convert tryptophan into serotonin, a hormone closely associated with increased mental energy and elevated mood. As with most weight-loss drugs, patients are warned that it only works in conjunction with a calorie-restricted diet and the expenditure of energy through regular exercise.

Several Russian medical institutions have also noticed how, in pediatric patients, vitamin D deficiency lines up with obesity and metabolic syndrome, and they have been working on this, too. Their research…

[…] demonstrates the role of vitamin D insufficiency in immune reactions resulting in development of subclinical inflammation in fat tissue infiltrated with macrophages and lymphocytes. It also shows […] the function of vitamin D as an endocrine and paracrine regulator of the process of inflammation in adipose tissue.

The body is constantly engaged in transforming vitamin D into biologically active metabolites that do a lot of things. As it turns out, D is “not a vitamin in the classical interpretation,” but a “steroidal prehormone with autocrine, paracrine and endocrine action.”

The latest research is a meta-analysis from the University of Bahrain based on many scientific papers about “the effects of vitamin D supplementation (cholecalciferol or ergocalciferol) on weight loss through holistic measurements of Body Mass Index (BMI), weight and waist.”

Like any reputable meta-study, this one is careful to explain its own limitations. It does not solve all the world’s problems, but helps to lay a foundation. The foundation would be a definition of the feasibility of cholecalciferol D as a new weight-loss drug. One roadblock is, nobody knows yet exactly how it does what it does. Simone Perna writes,

A recent study has reported that cholecalciferol has physiological and biochemical effect in a way that reduces metabolic abnormalities and tissue damage that can result from adiposity. Cholecalciferol has a direct role in suppressing the PTH hormone, which promotes and triggers fat accumulation in the adipose tissue via increasing intracellular calcium.

Or, it may be that cholecalciferol helps the intestines absorb calcium. Or the magic may lie in the way it excites the insulin receptors and maintains calcium at the proper levels. Still, the authors take a strong stand:

Prescribing cholecalciferol and following an effective strategy for cholecalciferol supplementation should be an imperative practice, especially for overweight and obese individuals.

Your responses and feedback are welcome!

Source: “5 Ways Vitamin D Can Benefit Weight Loss,” Vitagene.com, 09/28/18
Source: “Vitamin D Insufficiency in Overweight and Obese Children and Adolescents,” NIH.gov, 03/01/19
Source: “Is Vitamin D Supplementation Useful for Weight Loss Programs? A Systematic Review and Meta-Analysis of Randomized Controlled Trials,” MDPI.com, 07/12/19
Photo credit: Carol VanHook on Visualhunt/CC BY-SA

Why Vitamin D?

Most people have a vague idea that, if a nutrient was named after one of the first letters of the alphabet, it must be important, which is a fair assumption. We need vitamin D for bone health, muscle function, and an effective immune system, followed by a lot of “maybes.” In other words, the jury is still out on vitamin D as a cancer preventer, or a treatment for diabetes or multiple sclerosis.

Where does it come from? This sounds crazy, but when ultraviolet light from the sun hits our skin, it somehow causes the body to produce a “group of fat-soluble secosteroids.” We can also consume our vitamin D in a more conventional way, through eating food. Certain fish and their derivatives (e.g. cod liver oil) are replete with it. Beef liver, eggs, and Swiss cheese have a lot of it, too. Orange juice, milk, margarine, and yogurt tend to come fortified with vitamin D as an additive. It is of course available in capsules as a supplement.

Are obesity and vitamin D in a relationship? The question has been around for years, in a form that describes many medical mysteries: Which came first, the chicken or the egg? People have wondered whether vitamin D deficiency contributes to obesity, or is somehow caused by it. Catherine Peterson, Ph.D., wrote,

Data accumulated over the last decade have lead researchers to speculate that the vitamin D deficiency epidemic may be a major contributor to many obesity-associated complications such as the metabolic syndrome and diabetes.

The lack of vitamin D had been linked to respiratory tract infections, autoimmune diseases, and unhealthy bones. By 2018, it was suspected that having enough of it might protect humans against heart failure, cancer, and diabetes.

In Denmark, research by Copenhagen University Hospital and the Novo Nordisk Foundation revealed vitamin D deficiency to be common among obese children and adolescents.

Using data from the Netherlands Epidemiology of Obesity study on thousands of men and women aged 45–65, researchers looked specifically at where fat tends to settle. The four possibilities are total fat; belly fat (a.k.a. abdominal subcutaneous adipose tissue); fat that encases the internal organs (visceral adipose tissue); and hepatic fat, which collects inside the liver. According to the study results,

They discovered that in women, both total and abdominal fat were associated with lower vitamin D levels, but that abdominal fat had the greatest impact. In men, however, lower vitamin D levels were significantly linked with fat in the liver and abdomen.

And yet, the question remained unanswered: “Does a deficiency in vitamin D cause fat to be stored in the abdominal region, or does belly fat decrease the organism’s levels of vitamin D?”

Greek researchers determined that when overweight and obese children were given vitamin D supplements for a year, they had “significantly lower body mass index, body fat and improved cholesterol levels,” implying the promotion of weight loss and the reduction of risk factors related to heart disease and metabolic disease.

By 2018, it had been confirmed that the blood and most of the body’s organs contain receptors for vitamin D. It helps the body retain some minerals and prevents over-absorption of signaling chemicals. The question seemed to be settled:

Unfortunately, people who are obese also have a greater risk of developing a vitamin-D deficiency. Inversely, research now suggests that consuming up to 4,000 IU of vitamin D can benefit weight loss.

Your responses and feedback are welcome!

Source: “Vitamin D & Vitamin D Deficiency,” ClevelandClinic.org, undated
Source: “Vitamin D Deficiency & Childhood Obesity: A Tale of Two Epidemics,” NIH.gov, February 2014
Source: “Obesity is associated with vitamin D deficiency in Danish children and adolescents,” NIH.gov, 01/26/18
Source: “Belly fat linked to vitamin D deficiency,” MedicalNewsToday.com, 05/21/18
Source: “Vitamin D supplements may promote weight loss in obese children,” EurekAlert.org, 09/27/18
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Are the Weight-loss Drugs Worth It?

Weight-loss drugs work by different methods, and people often react to them differently. The phrase “Doctor’s orders” is well-known for a reason. A patient is often told to start off slowly and follow the expert’s guidance about when, and by how much, to increase the dosage. As with many other types of medication, several brands might need to be road-tested.

Childhood Obesity News has spoken of several weight-loss drugs, some with rather disturbing side effects. A report from Harvard Health Publishing mentions a few that had to be withdrawn from availability:

Dexfenfluramine and fenfluramine were taken off the market after they were linked to heart valve damage. Sibutramine (Meridia) was removed after it was linked to heart attack and stroke in people at highest risk for them.

But not all are dangerous, especially when prescribed by a conscientious doctor to a patient who gives a complete history, and follows instructions. Also, even serious side effects have to be accepted in some cases, when a comorbidity, or the obesity itself, is more threatening than the risk posed by the pharmaceutical. Under optimal conditions and with mindful compliance, what can be expected from weight-loss drugs? The Harvard report says,

When they are successful, they result in an average weight loss of about 5% over a period of six to 12 months.

So if the starting point is 200 pounds, 5 percent of that is 10 pounds. Down to 190, and it might take a year. Or, a person could just give up eating potato chips, or putting sugar in their tea. The potential for frustration can be reduced by careful assessment ahead of time.

The physician needs to know everything about the patient’s family history, current medications, allergies, and all those other boring but potentially crucial details. Not surprisingly, a vast number of patients also want to be fully informed before they commit to anything.

Aside from patients themselves, many wonderful folks act as advocates for relatives or friends who are not equipped to look out for their own interests. Sadly, a doctor simply does not have time to educate people in either breadth or depth, and may not have a staff member competent to do it either. In short, anyone who thinks about asking for a prescription must not expect a personal course in Weight-Loss Meds 101.

Frequently, the patient will be handed a sheaf of paper, which is a thoughtful gesture, but often futile, for a variety of reasons we will not attempt to explore here. In the main, those are printed-out web pages, carefully chosen by the doctor, to be sure — but still, information that a computer-literate person can obtain. Rather than wait, a person could do some research, highlight the most important factor, formulate one succinct, intelligent question for the doctor, and quite possibly receive an answer.

The bad news

For the non-professional who looks things up on the web, the most important part is, “Don’t use this if you have one of the named conditions, or if you take one of these other medications.” Say you’ve heard tell of Contrave, and you want to know what’s up. Some respectable institutions collate this kind of information. A web search for the product name plus “Mayo Clinic” brings up a page titled “Naltrexone and Bupropion (Oral Route).” Those are the two generic ingredients in the pills.

From there, the visitor is guided to a page enumerating more than 50 drugs that Contrave must not be taken with, and about a million more combinations that are recommended only in extreme need. Another list names a couple of dozen pre-existing conditions that should rule out the use of this compound.

By the way, what about non-prescription or over-the-counter weight loss pills? They are likely to contain caffeine and similar diuretic substances. In the context of genuine change, water loss is meaningless and potentially dangerous.

Your responses and feedback are welcome!

Source: “Are Weight-Loss Drugs Worth Trying?,” Harvard.edu, 05/22/18
Source: “Naltrexone and Bupropion (Oral Route),” MayoClinic.org, undated
Photo credit: Marcin Wichary on Visualhunt/CC BY

The Struggle for Pharmaceutical Legitimacy

This continues the saga of one particular medication, beloranib. In 2013, writer Esha Dey had warned, “Even if all goes well, the drug is years away from hitting the market.” All did not go well.

In October of 2014 a patient died of pulmonary (lung) blood clots. The Food and Drug Administration (FDA) placed a partial clinical hold on the trials, and now the manufacturer experienced trials in other senses of the word, from challenges to tribulations. The company had to step up its safety game, and choose participants unlikely to suffer adverse reactions.

But in January of 2015, another patient died from the same cause as the first one — despite having been extensively screened. The FDA responded by placing a complete hold on Zafgen’s operations, and ordered an investigation which, as journalist Sy Mukherjee suggested, might “doom any hopes the investigational compound had for regulatory clearance.” He also wrote,

It’s important to note that a direct link between the drug and the blood clots/deaths has not been incontrovertibly established — but the fact that several patients in studies involving beloranib have reported blood clots isn’t encouraging.

A month later, the same reporter caught up on the story:

The data that was released on Wednesday stems from 74 patients who had completed the phase 3 trial before the FDA’s hold and another 27 who had completed at least three-quarters of the trial. Specifically, the data showed significant body weight reductions (9.45% weight loss at a 2.4 mg dose and 8.2% loss at 1.8 mg) and reduced the urge to overeat associated with Prader-Willi syndrome.

[T]he company will have to convince the FDA that the screens and risk mitigation strategies are stringent enough to ensure patient safety.

Zafgen tweaked the formula, and the focus changed to diabetes, which is a much larger market, and pretty well saturated already by anti-diabetes drugs that can be taken orally. Beloranib needs to be injected, and although subcutaneous is not quite as bad as intramuscular, an awful lot of people would rather swallow a pill than puncture themselves.

Halfway through 2017, Science Translational Medicine writer Derek Lowe referenced the original mission and noted:

The benefits of going after an unusual population like Prader-Willi patients is that they are easy to identify and there is no medical treatment available. You will be the first to ever help them, and demonstrating that benefit should be a pretty straightforward proposition, clinically. Diabetes, on the other hand, is trickier.

[T]here’s a lot of competition — a whole list of drugs and a whole list of different mechanisms. It’s a crowded field with plenty of options, and making one’s way in it is going to be a lot harder (and a lot more costly) than it is in a rare disease.

This new iteration of beloranib was problematic because anti-diabetes drugs have especially high standards, and testing for cardiovascular outcomes is very costly. The drug did not have a good thrombotic safety profile, and the FDA “cited the possibility of cardiovascular safety risk.” Reporting for FierceBiotech, Nick Paul Taylor write,

The FDA has placed a clinical hold on Zafgen’s ZGN-1061. Zafgen has spent the past year putting that idea to the test in a phase 2 trial of ZGN-1061 in patients with Type 2 diabetes. The brief statement from Zafgen offers few clues about how long the clinical hold will be in place.

Things got up and running again, but the researchers tried out another compound that had a toxic effect on muscle tissue that had not shown up in previous formulations. Also, Lowe wrote,

There’s not much clarity on how (or if) the clinical hold on ZGN-1061 could be resolved, and it may in fact be unresolvable… [T]hey have quite a hole to climb out of at this point.

Your responses and feedback are welcome!

Source: “CORRECTED — New entrant in obesity drug race targets body, not the mind,” Reuters.com, 08/26/13
Source: “UPDATE: FDA places complete hold on Zafgen obesity med trials after 2nd patient death,” BioPharmaDive.com, 12/03/15
Source: “After patient deaths, new Zafgen obesity med data revives approval hopes,” BioPharmaDive.com, 01/21/16
Source: “Zafgen’s Second Act,” ScienceMag.org, 05/08/17
Source: “FDA hits Zafgen’s beloranib successor with clinical hold,” FierceBiotech.com, 11/26/18
Source: “Zafgen: Will There Be a Third Act?,” ScienceMag.org, 03/14/19
Photo credit: Barry Silver on Visualhunt/CC BY

An Injectable Raises, and Dashes, Hopes

Some drugs work better, or only, in injectable form. Turn back the clock six years, to what was said then about beloranib. Science looked for a cure that would make the body produce less fat, and burn more of what it did make, for fuel. This result was earnestly desired, to ease the torture of insatiable hunger experienced by patients with Prader-Willi syndrome.

Reporting for Reuters, Esha Dey wrote,

Beloranib works by blocking an enzyme known as methionine aminopeptidase 2, or MetAP2, which plays a key role in the production and use of fatty acids.
[It] leads to a higher rate of fat burn and improves some key conditions related to heart safety, including reducing bad cholesterol and lowering inflammatory actions in the body.

The drug’s safety profile was, at that time, considered impressive. Were there side effects? Of course — mainly nausea, vomiting, and sleep disturbance. But on the up side, subjects given the highest dose lost an average 22 pounds in three months. An on the very far up side, the subjects “continued their normal food and exercise habits.”

If that aspect proved out, it would be an enormous selling point — perhaps even worth the daily needle sticks. Also, the injection concept might be an easier sell because it is subcutaneous, the kind where a hunk of skin is pinched up, rather than intramuscular.

The strategy

One might have wondered, at the time, why go to so much trouble for Prader-Willi syndrome, a non-mainstream condition with a genetic basis? When a product affects only one out of around 13,000 people, can it possibly return even a fraction of the investment that was made in it?

A big corporation has money to experiment with, but why the interest in such a rare disease? Besides, the way things have been going, the condition might more easily be amenable to genetic manipulation, which would eliminate the need for medication.

On the other hand, the body’s fat metabolization is a subject of lasting interest to many populations. Years later, Derek Lowe wrote for Science Translational Medicine,

I feel sure that the way it was supposed to work was that beloranib was going to demonstrate its use in the Prader-Willi population, where it wouldn’t be so hard to demonstrate benefit and approval had much better chances. Then it (or a followup) could go for the larger diabetes market, using the rare disease revenue stream. This is a common strategy: get a foothold in the smaller, underserved patient population and then try to expand.

There is nothing sneaky about this tactic. It just happens to be the way these things work. Research funding is the pot of gold at the end of many exploratory rainbows, and sometimes the most direct path is not the path that leads there. For good or ill, human institutions can only do so much. Even the best efforts may be thwarted by the inexorable forces of nature.

(To be continued…)

Your responses and feedback are welcome!

Source: “CORRECTED — New entrant in obesity drug race targets body, not the mind,” Reuters.com, 08/26/13
Source: “Zafgen’s Second Act,” ScienceMag.org, 05/08/17
Photo credit: Internet Archive Book Images on Visualhunt/No known copyright restrictions