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Is Bile Acid Metabolism Altered in Obesity?

bile acid metabolismRecent interest in the role of the gut microbiome as well as the alterations in gut physiology that happens with bariatric surgery, have prompted an increasing interest in the biology of bile acids and how they relate to metabolism.

As I distinctly recall from my medical textbooks, the biology of bile acid production and disposition (let alone its many functions within the gut and in the circulation) are anything but simple.

This is why much about how bile acid physiology, especially in relationship to glucose metabolism and obesity remains unclear.

Now, a study by Rebecca Heuseler and colleagues, published in the Journal of Clinical Endocrinology and Metabolism, points to some differences in bile acid production and physiology in individuals with obesity.

In a series of studies, fluctuations in bile acid levels ere measured in 11 nonobese and 32 obese subjects; Bile acid transporter expression in liver specimens were measured in 42 individuals and in specimens of duodenum, jejunum, ileum, colon, and pancreas from 9 individuals.

Measurements were conducted after overnight fasting, during a hyperinsulinemic-euglycemic clamp, or a mixed meal tolerance test.

Markers of bile acid synthesis were twofold higher in subjects with obese subjects and inversely correlated with insulin sensitivity.

While insulin infusion (during the euglycemic clamp) acutely reduced serum bile acids in nonobese subjects, but this effect was blunted in obese subjects.

Subjects with a higher BMI also experiences a blunted rise in serum serum bile acids following a meal compared to non-obese subjects.

What all of this means is largely unclear but as the authors note,

“The findings reveal new pathophysiological aspects of bile acid action in obesity that may lend themselves to therapeutic targeting in metabolic disease.”

Perhaps this is a space to watch.

@DrSharma
Edmonton, AB

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If Oprah Can’t Why Do You Think You Can?

sharma-obesity-oprah1There are no doubt long-term “success stories” out there – people who just by making (often radical) changes in their diet and activity behaviours have lost a substantial amount of weight AND are keeping it off.

However, there is also no doubt that these people are rare and far between – which is exactly what makes each one of them so exceptional.

I am not speaking of all the people we hear or read about who have lost tons of weight – we hear about their spectacular weight loss – cutting carbs, cutting gluten, going vegan, going paleo, alternate day fasting, running marathons, training for iron man competitions, going on the Biggest Loser or eating at Subway.

What we don’t hear about is the same people, when they put the weight back on – which, in real life is exactly what happens to the absolutely vast majority of “losers”. We hear of their “success” and then we never hear from them again – ever.

Oprah is different! Different because, we have had the opportunity to follow her ups and downs over decades.

When Oprah “succeeds” in losing weight, she does not disappear into the night – no – she puts the weight back right in front of our eyes, again and again and again and again.

Now, comedy writer Caissie St.Onge, in a comment posted on facebook, pretty much summarizes what it is we can all learn (and should probably have learnt a long time ago) from Oprah:

“Oprah is arguably the most accomplished, admired, able person in the world. She creates magic for other people and herself on the regular. So, if Oprah can’t do permanent lifelong weight loss, maybe it can’t be done. Oprah is also crazy rich. If Oprah can’t buy permanent lifelong weight loss, maybe it can’t be bought.”

“I’m not saying you should give up on your dreams of having the body you want. I’m just asking, if you never get that waist, will your life have been a waste? (I see what I did there.) Every day we are bombarded with media, content and products. Special foods and drinks. Programs and plans. None of this shit has ever worked for Oprah and it probably isn’t gonna work for me or you.”

“I know the reason isn’t because you’re weak. If you’re carrying around 10 or 20, or 50 or 150 pounds more than the tiny friend who always calls herself fat in front of you and you don’t kick her in the back of the knee, you’re the opposite of weak. You’re very, very strong in at least two different kind of ways.”

“I realize there are people who are DYING to tell you what they think about what you should do with your body. It always starts with, “No offense but…” or “Not to be mean, but…” And it’s always offensive and mean, but also, you probably say things to yourself every day that are way meaner than what any “well-intentioned” “friend” or internet troll could come up with. You’re gonna have to try harder if you want to beat us at our own game, internet trolls. I would pop someone in the chops if they spoke to me the way I speak to myself. And I would bet all of Oprah’s money that Oprah says mean shit to herself too. Oprah does.”

“You can do what you want. You knew that. But I’m gonna stop wishing that I didn’t have dimples on the backs of my hands or that my ankles were more flattered by strappy shoes. I’m gonna stop telling people that they look great and start telling them what I really mean, that’s it’s nice to see them. And I see you. And I like you so much just how you are right now, and not a year or five years from now when you may or may not be smaller….. Oprah. I’ll love you either way.”

Cassie’s entire post is available here

@DrSharma
Edmonton, AB

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When To Use Metabolic Carts In Clinical Practice

metabolic cartCaloric requirements are generally estimated using formulas that use age, sex, and weight as variables. While these formulas provide a rough estimate, they are notoriously unreliable in a number of clinical situations, especially in critically ill patients, where under or over nutrition can substantially influence outcome.

A more precise way to measure caloric requirement involves the use of the so-called metabolic cart, where energy requirements are indirectly measured based on CO2 production.

A paper by Pierre and Joelle Singer, published in Nutrition in Clinical Practice now discusses the various situations where measurement of energy requirements using indirect calorimetry may be deemed to be essential for good clinical care.

These situations include patients in ICU, especially patients with sepsis or chronic pulmonary disease, or those that appear malnourished.

In obesity, the authors note that

“Energy requirements are difficult to define in these patients since their lean body mass, which determines the REE, may decrease, increase, or be normal, and fat may also contribute to variability in REE.”

Thus, measuring metabolic rate should be the gold standard as

“…actual body weight is likely to overestimate needs, while ideal body weight will underestimate them.”

The paper also discusses the practical limitations and potential pitfalls of using indirect calorimetry in various practice situations.

Unfortunately, the paper does not discuss the potential utility of measuring REE in obesity management, including the post-bariatric surgery patients, where current equations do not provide accurate estimates.

Nevertheless, the paper is certainly an interesting read for clinicians, who want to better understand when to use indirect calorimetry to monitor and adjust energy requirements in critically ill patients.

@DrSharma
Edmonton, AB

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Promising Data For Setmelanotide For Genetic Obesity

rhythm logoOne of the most common genetics variations related to obesity found in the general population involves the melanocortin-4  (MC4) receptor, which plays  a key role in appetite regulation.

Now Rhythm Pharmaceuticals released its first data on the use of their novel MC4-R agonist setmelanotide in patients with obesity and proven MC4-R defects.

According to their press release,

“In this pilot study, obese (BMI >/= 30kg/m2) patients with a heterozygous MC4R loss-of-function mutation were enrolled in a double-blind, placebo-controlled, randomized, parallel-group study for 4 weeks.  Eight patients (six active, two placebo) received placebo or RM-493 at 0.01 mg/kg/day (~ 1 mg/day) by continuous subcutaneous infusion. Key endpoints were safety, weight loss, waist circumference, and caloric intake. Setmelanotide was well tolerated over 4 weeks, with no serious adverse events or discontinuations. The most common side effects were headache and skin tanning, with the latter believed to be due to off-target activity at the related melanocortin-1 receptor. Setmelanotide demonstrated strong trends for placebo-subtracted weight loss (2.62 kg; p=0.088); WC (5.1 cm; p=0.188) and daily caloric intake (351 kCal/day; p=not significant), without clinically important effects on heart rate or blood pressure.”

Overall, the company has taken (the perhaps wise) option of focussing their development program on genetic forms of obesity.

Currently they have an ongoing Phase 2 setmelanotide trial for the treatment of Prader-Willi syndrome and a second Phase 2 trial for the treatment of pro-opiomelanocortin (POMC) deficiency obesity, a very rare, life-threatening genetic disorder of the MC4 pathway associated with unrelenting appetite and obesity.

Clearly, this will be a space to watch.

@DrSharma
Edmonton, AB

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Effect Of Sleep Deprivation And Meal Timing On Insulin Sensitivity

sharma-obesity-sleep-deprivationAs we continue learning more about the complexity of appetite and energy balance, sleep and circadian rhythm are emerging as important variables.

Now a study by Robert Eckel and colleagues, published in Current Biology, illustrates how sleep deprivation and timing of meals can markedly alter insulin sensitivity.

Studies were conducted in 16 healthy young adults (8w) with normal BMI. Following a week of 9-hr-per-night sleep schedules, subjects were studied in a crossover counterbalanced design with 9-hr-per-night adequate sleep (9-hr) and 5-hr-per-night short sleep duration (5-hr) conditions lasting 5 days each, to simulate a 5-day work week. Sleep was restricted by delaying bedtime and advancing wake time by 2 hr each.

Energy balanced diets continued during baseline, whereas food intake was ad libitum during scheduled wakefulness of 5- and 9-hr conditions.

Overall, the simulated 5-day work week  of 5-hr-per-night sleep together with an ad libitum diet resulted in a 20% decrease in oral and intravenous insulin sensitivity, which was compensated for by increased insulin secretion..

These changes persisted for up to 5 days after restoring 9-hr sleep opportunities.

The authors also showed that shifting circadian rhythm resulted in morning wakefulness and eating during the biological night, a factor that may promote weight gain over time.

 

These findings have important implications not just for shift workers but for all of us, who may not be getting adequate amounts of restorative sleep.
Paying more attention to sleep and its impact on appetite and metabolism may need to find its way into routine clinical practice.
@DrSharma
Vienna, Austria
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