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Can Liraglutide Help Grow New Fat Cells?

The human GLP-1 analogue liraglutide is now approved for the long-term medical treatment of obesity in an ever-increasing number of countries. Its safety and clinical effectiveness is now well established and there is no doubt that this is an important addition to the rather limited number of treatment options available to people living with obesity.

Interestingly, however, liraglutide has also been shown to promote the differentiation of pre-adipocytes or, in other words, promote the formation of new fat cells.

While this may seen worrying or even counter-intuitive, we much remember that having more (smaller) rather than fewer (bigger) fat cells actually has substantial metabolic advantage s- there is indeed ample data showing that large adipocyte cell size and limited capacity to grow fat cells (the extreme case of which is seen in people with lipodystrophy) is actually a key risk factor for metabolic problems including insulin resistance, possible by promoting the accumulation of ectopic fat (e.g. in liver and skeletal muscle).

Now, a paper by Yongmei Liand colleagues, published in Molecular Medicine Reports provides additional insight into the cellular pathways involved in liraglutide’s adipogenic effects.

Using a series of in vitro experiments, the researchers show that liraglutide does indeed promote the adipogenic differentiation of 3T3-L1 cells (a widely used murine preadipocyte cell line)  through a process that upregulates the expression of C/EBPα and PPARγ at the early phase of adipogenic differentiation, promots the expression of lipogenesis associated genes including aP2, and enhances the accumulated of lipids.

At the same time, liraglutide appears to suppress cell proliferation via the Hippo‑yes‑associated protein (YAP) signaling pathway, thereby allowing these cells to transform into mature adipocytes sooner.

How relevant these observations are for humans remains to be seen, but certainly the promotion of adipogenic differentiation may hold the potential for improving insulin sensitivity and reducing the metabolic risks associated with excess weight gain.

@DrSharma
Edmonton, AB

Disclaimer: I have received speaking and consulting honoraria from Novo Nordisk, the maker of liraglutide.

 

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Molecular Changes During Weight Gain – Everyone Is Different

As one may well imagine, changes in body weight (up or down) can profoundly affect a vast number of hormonal and metabolic pathways.

Now, a team of researchers led by Brian Piening and colleagues, in a paper published in Cell Systems used a broad “omics” based approach to study what happens when people lose ore gain weight.

Specifically, the goal of this study was to:

(1) assemble a comprehensive map of the molecular changes in humans (in circulating blood as well as the microbiome) that occur over the course of a carefully controlled weight gain and their reversibility with weight loss; and

(2) determine whether inulin sensitive (IS) and insulin resistant (IR) individuals who are matched for degree of obesity demonstrate unique biomolecular signatures and/or pathway activation during similar weight gain.

The study included 23 carefully selected healthy participants with BMI 25–35 kg/m2, were studied. Samples were collected at baseline. They then underwent a 30-day weight gain period (average 2.8 kg), followed by an eucaloric diet for 7 days, at which point a second fasted sample of blood and stool was collected. Each participant then underwent a caloric-restricted diet under nutritionist supervision for a subsequent 60-day period designed to return each participant back to his/her initial baseline weight, at which point a third set of fasted samples of blood and stool were collected. A subset of participants returned for a follow-up sampling approximately 3 months after the end of the perturbation.Insulin resistance was assessed at baseline using a modified insulin suppression test.

The large-scale multi-omics assays performed at all time points on each participant included genomics, proteomics, metabolomics and microbiomics.

Despite some differences between the IS and IR group (particularly in differential regulation of inflammatory/immune response pathways), overall, molecular changes were dominated by inter-personal variation (i.e. changes within the same individual), which accounted for more than 90% of the observed variance in some cases (e.g., cytokines). The most striking changes with weight gain were in inflammation response pathways (despite the rather modest weight gain) and were (fortunately) reversed by weight loss.

As the authors note,

“Comparing the variation in cytokine levels between multiple baselines in a single individual versus across individuals, we observed a striking difference: for almost all cytokines, the within-individual coefficient of variation was under 20%, whereas the variation across individuals was 40%–60%. This shows that our baseline cytokine profiles are unique to the individual, a point that has significant implications for one-size-fits-all clinical cytokine assays for the detection and/or monitoring of disease.”

On the opposite side of the spectrum, proteomics and metabolomics measurements had a substantial unexplained component (30% and 35%, respectively), highlighting the presence of unaccounted factors (e.g., food, exercise, and other changing environmental factors) or a subject-specific reaction to the perturbation.

Notably, not all of the responses we observed were consistent across IR and IS participants.

“In particular, for the microbiome, we observed that the microbe A. muciniphila was weight gain responsive only in insulin-sensitive participants. The abundance of this particular microbe in IR individuals did not change across perturbations and was barely or not detectable in most IR individuals.”

Clearly, these findings highlight the fact that each individual is biochemically unique, which the authors note, makes a strong case for personalized analysis in medicine.

Perhaps more importantly for researchers, nearly all of the data are publicly available, enabling exploration of inter-omic relationships and alterations across a longitudinal perturbation, thus providing a valuable resource for the development and validation of bioinformatic tools and pipelines integrating disparate data types.

@DrSharms
Edmonton, AB

 

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How The Body Weighs Itself – Evidence For A Bone “Gravitostat”

In my talks, I have often joked about how to best keep weight off – just carry around a backpack that contains the lost pounds to fool the body into thinking the weight is still there.

It turns out that what was intended as a joke, may in fact not be all too far from how the body actually regulates body weight.

As readers of these posts are well aware, body weight is tightly controlled by a complex neuroendocrine feedback system that effectively defends the body against weight loss (and somewhat, albeit less efficiently, protects against excessive weight gain).

Countless animal experiments (and human observations) show that following weight loss, more often than not, body weight is regained, generally precisely to the level of initial weight.

With the discovery of leptin in the early 90s, an important afferent part of this feedback system became clear. Loss of fat mass leads to a substantial decrease in leptin levels, which in turn results in increased appetite and decreased metabolic rate, both favouring weight regain and thus, restoration of body weight to initial levels.

Now, an international team of researchers led by John-Olov Jansson from the University of Gothenburg, Sweden, in a paper published in the Proceeding of the National Academy of Science (PNAS), provides compelling evidence for the existence of another afferent signal involved in body weight regulation – one derived from weight-bearing bones.

Prompted by observations that prolonged sedentariness can promote weight gain, independent of physical activity, the researchers hypothesised that,

“…there is a homeostat in the lower extremities regulating body weight with an impact on fat mass. Such a homeostat would (together with leptin) ensure sufficient whole body energy depots but still protect land-living animals from becoming too heavy. A prerequisite for such homeostatic regulation of body weight is that the integration center, which may be in the brain, receives afferent information from a body weight sensor. Thereafter, the integration center may adjust the body weight by acting on an effector.”

In a first series of experiments, the researchers observed that implanting a weight corresponding to about 15% of body weight into rodents (rats and mice), resulted in a rapid “spontaneous” adjustment in body weight so that the combined weight of the animal plus the weight implant corresponded more-or-less to that of control animals.

Within two weeks of implanting the weights, ∼80% of the increased loading was counteracted by reduced biological weight, largely due to reduced white adipose tissue (WAT), accompanied by a corresponding decrease in serum leptin levels. (Interestingly, this weight loss was also accompanied by a substantial improvement in insulin resistance and glucose homeostasis).

The decrease in “biological” body weight was mainly attributable to a reduction in caloric intake with no changes in fat oxidation, energy expenditure or physical activity.

Removal of the implanted weights resulted in rapid weight regain to initial levels, showing that the “weight sensor” was active in both directions.

Experiments showed that this “weight sensing” mechanism was largely independent of the leptin pathway and did not appear to involve grehlin, GLP-1, a-MSH, estrogen receptor-a, or the sympathetic nervous system.

Now for the interesting part: the observed effect of weight loading was not seen in mice depleted specifically of DMP1 osteocytes, demonstrating that the suppression of body weight by loading is dependent on osteocytes.

As the authors note, these findings are consistent with a growing body of data indicating that the skeleton is an endocrine organ that regulates energy and glucose metabolism. Indeed, it is well known that osteocytes can sense dynamic short term high-impact bone loading for local bone adaptation – now it appears, that osteocytes may also play a vital role in sensing overall body weight and signalling this to the brain centres that regulate energy balance and body weight.

Thus, in summary, not only have the authors provided compelling evidence for a “weight-sensing” role for bone osteocytes (presumably through their presence in the long weight-bearing bones of our lower extremities) but also provide a plausible biological explanation for the weight gain and change in fat mass seen with prolonged sedentariness (which literally takes the weight off the bone).

These findings may also finally explain why rats held at increased gravity for extended periods of time (simulated G2) become lean even when their energy intake matches their expenditure.

Perhaps, carrying around a heavy backpack may indeed help with long-term weight loss maintenance after all – who knew?

@DrSharma
Berlin, D

Hat tip to Jean-Philippe Chaput for alerting me to this article

 

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Free Webinar: Assessing Body Fat – Taking Obesity Phenotyping To The Next Level

As readers will be well aware, n terms of health risks, fat is not fat is not fat is not fat.

Rather, whether or not body fat affects health depends very much on the type of body fat and its location.

While there have been ample attempts at trying to describe body fat distribution with simple anthropometric tools like measuring tapes and callipers, these rather crude and antiquated approaches have never established themselves in clinical practice simply because they are cumbersome, inaccurate, and fail to reliably capture the exact anatomical location of body fat. Furthermore, they provide no insights into ectopic fat deposition – i.e. the amount of fat in organs like liver or muscle, a key determinant of metabolic disease.

Recent advances in imaging technology together with sophisticated image recognition now offers a much more compelling insight into fat phenotype.

In this regard, readers may be interested in a live webinar that will be hosted by the Canadian Obesity Network at 12.00 pm Eastern Standard Time on Thu, Nov 23, 2017. The webinar provides an overview of a new technology developed by the Swedish company AMRA,  that may have both important research and clinical applications.

The talk features Olof Dahlqvist Leinhard, PhD, Chief Scientific Officer & Co-Founder at AMRA and Ian Neeland, MD, a general cardiologist with special expertise in obesity and cardiovascular disease, as well as noninvasive imaging at the UT Southwestern Medical Center in Dallas, US.

Registration for this seminar is free but seats are limited.

To join the live event register here.

I have recently heard this talk and can only recommend it to anyone interested in obesity research or management.

@DrSharma
Edmonton, AB

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The Key To Obesity Management Lies In The Science Of Energy Homeostasis

If there is one thing we know for sure about obesity management, it is the sad fact, that no diet, exercise, medication, not even bariatric surgery, will permanently reset the body’s tendency to defend and regain its body weight to its set point – this generally being the highest weight that has been achieved and maintained for a notable length of time.

Thus, any effective long-term treatment has to offset the complex neurobiology that will eventually doom every weight-loss attempt to “failure” (no, anecdotes don’t count!).

Just how complex and overpowering this biological system that regulates body weight is, is described in a comprehensive review by the undisputed leaders in this field (Michael Schwartz, Randy Seeley, Eric Ravussin, Rudolph Leibel and colleagues) published in Endocrine Reviews. Indeed the paper is nothing less than a “Scientific Statement” from the venerable Endocrine Society, or, in other words, these folks know what they’re talking about when it comes to the science of energy balance.

As the authors remind us,

“In its third year of existence, the Endocrine Society elected Sir Harvey Cushing as President. In his presidential address, he advocated strongly in favor of adopting the scientific method and abandoning empiricism to better inform the diagnosis and treatment of endocrine disease. In doing so, Cushing helped to usher in the modern era of endocrinology and with it, the end of organo-therapy. (In an interesting historical footnote, Cushing’s Energy Homeostasis and the Physiological Control of Body-Fat Stores presidential address was given in , the same year that insulin was discovered.)”

Over 30 pages, backed by almost 350 scientific citations, the authors outline in excruciating detail just how complex the biological system that regulates, defends, and restores body weight actually is. Moreover, this system is not static but rather, is strongly influenced and modulated by environmental and societal factors.

Indeed, after reading this article, it seems that the very notion, that average Jane or Joe could somehow learn to permanently overcome this intricately fine-tuned system (or the societal drivers) with will power alone is almost laughable (hats off to the very few brave and determined individuals, who can actually do this – you have climbed to the top of Mount Everest and decided to camp out there for the foreseeable future – I wish you all the best!).

Thus, the authors are confident that,

“The identification of neuromolecular mechanisms that integrate short-term and long-term control of feeding behavior, such that calorie intake precisely matches energy expenditure over long time intervals, will almost certainly enable better preventive and therapeutic approaches to obesity.”

Sadly, despite all we have learnt about this system, we are still far from fully understanding it. Thus, the canonical molecular/ cellular signaling pathway: LEP → LEPR → POMC, AgRP → PC → MC4R is just one pathway in a complex network of multiple interacting and sometimes redundant pathways that involve virtually every part of the brain.

Also, the effect of environmental factors appears to be far more complex than most people think. Thus,

“During sensitive periods of development, ontogenic processes in both brain and peripheral organs can be modified so as to match anticipated environmental conditions. Although many exposures during development could potentially predispose to obesity in adulthood, we focus here on two that some researchers think contribute to the secular trends in obesity: parental obesity and exposure to endocrine disrupting chemicals (EDCs).”

Throw in the role of gut bugs, infections, and societal factors, and it is easy to see why no simple solution to the obesity epidemic are in sight (let alone a range of effective long-term treatments like we have for most other common chronic diseases).

As for solutions,

“To be viable, theories of obesity pathogenesis must account not only for how excess body fat is acquired, but also for how excess body fat comes to be biologically defended. To date, the preponderance of research has focused on the former. However, we must consider the possibility that some (perhaps even most) mechanisms underlying weight gain are distinct from those responsible for the biological defense of excess fat mass. A key question, therefore, is how the energy homeostasis system comes to defend an elevated level of fat mass (analogous to the defense of elevated blood pressure in patients with hypertension). Answering this question requires an improved understanding of the neuro-molecular elements that underlie a “defended” level of body fat. What are the molecular/neuroanatomic predicates that help establish and defend a “set point” for adiposity? How do these elements regulate feeding behavior and/or energy expenditure, so as to achieve long-term energy balance? By what mechanisms is an apparently higher set point established and defended in individuals who are obese?” [sic]

Clearly,

“Given that recovery of lost weight (the normal, physiological response to weight loss irrespective of one’s starting weight) is the largest single obstacle to effective long-term weight loss, we cannot overstate the importance of a coherent understanding of obesity-associated alterations of the energy homeostasis system.”

There is much work to be done. Whether or not, in this climate of anti- and pseudo-science, funding for such fundamental work will actually be made available, is anyone’s guess.

@DrSharma
Edmonton, AB

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