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Friday, October 11, 2013

Neuronal Control of Appetite, Metabolism and Weight

Previous 7 days, I attended a Keystone conference, "Neuronal Handle of Urge for food, Metabolism and Weight", in Banff.  Keystone conferences are modest, targeted conferences that are inclined to draw in large top quality science.  This particular convention centered about my own specialist analysis passions, and it was amazingly educational.  This publish is a summary of some of the most salient factors.

Quick Rate of Scientific Development


The meeting genuinely underscored the incredible rate of scientific development on feeding, body bodyweight and fat burning capacity, and the essential part the mind performs in these procedures.  This is mainly due to impressive technical breakthroughs being used by folks who know how to use them to response important questions.  Conditional knockout and transgenic mice, in which genes can be manipulated in certain mobile sorts, keep on to engage in an crucial part in neuroscience study.  However, the more recent introduction of optogenetic and DREADD technologies has been a quantum leap.  Optogenetics (light-weight-activated ion channels) makes it possible for researchers to manipulate certain neuron populations utilizing mild, which delivers beautiful spatial and temporal handle.  This is important because  1) you can hearth (or inhibit) neurons in a way that about approximates how they would hearth normally, and two) even within very small sub-nuclei of your brain, there can be a number of diverse cell varieties doing diverse features, so obtaining a technique with mobile kind specificity is helpful (in distinction, imagine striving to decide the purpose of a nucleus by lesioning it, which may possibly demolish ten diverse intermingled cell populations all doing various issues).  One early instance of the software of optogenetics to feeding confirmed that activating AgRP neurons in the arcuate nucleus "evokes voracious feeding inside of minutes" (one).  AgRP neurons ended up currently known to be an important neuron inhabitants for hunger and feeding, but this experiment demonstrated it in the most convincing method to date.

DREADD channels are used to activate or inhibit neuron activity making use of injections of the artificial ligand CNO.  This is a good technique simply because it is non-invasive (as opposed to optogenetics).  DREADD engineering has bolstered the obtaining that activating AgRP neurons drives feeding and quick body fat obtain (2).

There are a quantity of other interesting rising systems, but individuals two stand out.

Palmiter Lab

Richard Palmiter (College of Washington) gave the opening keynote deal with, describing his investigation on a feeding circuit from AgRP neurons in the arcuate nucleus to the parabrachial nucleus and then the central nucleus of the amygdala.  This circuit looks to shut off food ingestion in response to aversive stimuli (sickness, ache, worry), but may possibly not perform a lot of a function in feeding under standard situation.

Dr. Palmiter also introduced the impressive finding that ablating AgRP neurons reverses the being overweight and infertility phenotype of ob/ob (leptin-deficient and genetically overweight) mice.

As the inventor of the transgenic mouse, Dr. Palmiter has performed a key position in advancing scientific development in the organic sciences.

Ozcan Lab

Umut Ozcan (Harvard University) introduced information from his lab suggesting that leptin resistance in the hypothalamus is induced by endoplasmic reticulum pressure (ER pressure a sort of mobile anxiety that can be caused by misfolded proteins).  He has utilized a compound (SR-01) in overweight mice that minimizes ER anxiety, restores leptin sensitivity and causes outstanding body fat reduction.  This compound has no result in genetically obese mice that lack leptin receptors, and it has no effect on lean mice, equally of which support his speculation that it especially will increase leptin sensitivity in diet regime-induced overweight mice.  He has been presenting these knowledge at conferences for likely on two a long time and they haven't been printed however, which I find puzzling.  But they surely do seem promising.

Lam Lab

Tony Lam (College of Toronto) offered his data on the function of glucagon in blood glucose manage by way of the mind.  Glucagon is an critical player in blood glucose handle through the liver, but its results have been generally assumed to end result from direct actions on the liver till Dr. Lam's findings.  He confirmed that glucagon also acts in the mind to regulate blood glucose, but in the reverse path to its actions in the liver (suppresses blood glucose), and that diet-induced overweight animals lose the capability to activate this mechanism, probably contributing to elevated blood glucose in weight problems.

Lowell Lab

Brad Lowell gave a remarkable talk.  His lab is concentrated on comprehending how AgRP and POMC neurons are controlled by other neurons.  As said above, this modest populace of neurons in the arcuate nucleus is the most strong feeding circuit recognized in the brain.  POMC neurons are a nicely-characterized neuron inhabitants in the arcuate nucleus that suppress feeding.  The Lowell lab utilizes a combination of neuron tracing tactics (tracing the brain's wiring diagrams), optogenetics, and electrophysiology (measuring the 'electrical' action of neurons), to excellent influence.

I will not go through the whole talk, which was incredibly info-dense, but I will point out two essential conclusions:

  1. What neurons activate AgRP neurons and lead to hunger and feeding?  PACAP and TRH eurons in the paraventricular nucleus deliver excitatory projections to AgRP neurons, and stimulating these neurons tremendously increases feeding.  The DMH also sends excitatory projections to AgRP neurons, but these are weaker.  

  2. The arcuate nucleus mediates a large part of leptin motion on urge for food and human body excess weight, however deleting leptin receptors from arcuate neurons does not lead to considerably obesity, implying that they are getting leptin-responsive alerts from upstream neurons.  What are these neurons?  Dr. Lowell showed that leptin receptor expressing neurons in the dorsomedial hypothalamus send dense inhibitory projections to AgRP neurons.  Activating these DMH neurons potently suppresses feeding.


Sternson Lab

Scott Sternson (NIH's prestigious Janelia farm campus) is intrigued in the downstream targets of AgRP neurons, and he also can make comprehensive use of optogenetics, DREADDs and related approaches.  Dr. Sternson argued for a paradigm change in understanding feeding-connected determination.  Activating AgRP neurons will increase motivation for meals, almost certainly reflecting hunger.  But what is starvation, and how does it condition future foodstuff variety behaviors (through reward processes)?  He introduced data suggesting that starvation drives meals consumption behavior and understanding by means of a approach involving unfavorable reinforcement.

He confirmed that activating AgRP neurons in mice (presumably inducing a starvation-like condition) is aversive (unpleasant).  Also, experimentally suppressing the activation of AgRP neurons caused by hunger is reinforcing/fulfilling (increases the likelihood of looking for situations/flavors connected with the cessation of AgRP neuron action), basically suggesting that the satiety condition is reinforcing because it relieves the disagreeable state of starvation.  So animals find out to choose circumstances associated with the relieving of the aversive 'hunger' condition, and this is element of how the reward technique learns how to guidebook food-in search of conduct

Zeltser Lab

Lori Zeltser (Columbia University) experienced a fascinating chat on anorexia that also contained a really interesting tibit on insulin and obesity.  I won't get into all the details of her speak, but she is investigating the intersection between genes, calorie restriction, and psychological pressure in selling anorexia.

The Val66Met allele of the BDNF gene is strongly connected with anorexia in at minimum some human scientific studies.  BDNF is component of the leptin signaling pathway and therefore performs an crucial function in the manage of food intake and human body fatness.  BDNF Val66Met mice are fairly standard, but when pressured (by social isolation) or briefly calorie-limited, mice will go by means of spontaneous periods of aphagia (no consuming).  I locate it exceptional that it's feasible to product anorexia in mice, but her data have been pretty convincing that this human genetic susceptibility aspect boosts the threat of anorexia beneath problems of psychological or metabolic pressure.  We do not know if the same is real in people, but it would seem plausible based mostly on her knowledge.

She offered yet another interesting tidbit that is appropriate to the insulin-weight problems thought: mice with a hypothalamus-particular deletion (Nkx2.one) of the insulin receptor have regular body excess weight, physique fatness, and leptin ranges.  The implication is that (complete) insulin resistance in the hypothalamus does not direct to leptin resistance or obesity, which bears on a single of the far more well-known versions of the insulin-being overweight hypothesis (e.g., the notion that hyperinsulinemia brings about hypothalamic insulin resistance, which triggers hypothalamic leptin resistance, which prospects to being overweight).

Cowley Lab

Michael Cowley (Monash College) gave one of the most fascinating talks, partly because I wasn't conscious of this line of investigation prior to the conference.  In limited, he has proven that elevated leptin is largely accountable for obesity-induced hypertension (substantial blood stress) in rodents, and the proof suggests the identical is correct for humans, who also tend to build hypertension with obesity.  He (with Stephanie Simonds) just lately wrote an superb assessment post in Traits in Neurosciences that handles most of the proof (3).  The illustrations of the sympathetic (SNS) and parasympathetic (PNS) anxious techniques, and the brain locations associated in SNS and PNS outflow are actually excellent in that paper.  I'll be hanging on to it as a reference.

The mind controls the SNS and PNS, which regulates several 'autonomic' (unconscious) features like heart rate, lipolysis, glucose control, adrenaline launch, warmth manufacturing, digestion, and blood force.  Normally, it does so in response to leptin and other peripheral indicators.  During the advancement of being overweight, the mind turns into resistant to several of leptin's steps, these kinds of as its capacity to suppress foods intake and minimize physique fatness.  However, it will not turn into resistant to leptin's potential to encourage the SNS, so the SNS goes into overdrive in obese rodents and people.  Dr. Cowley's info recommend that this is due in large component to enhanced leptin performing in the dorsomedial hypothalamus.

Insulin also activates the SNS, and obesity is also connected with elevated insulin.  Elevated insulin performing on the mind is also most likely a element that contributes to hypertension by means of equivalent pathways.  Interestingly, lower-carbohydrate eating plans often have a remarkable impact to speedily lessen blood pressure.  Dr. Cowley's benefits recommend that this is almost certainly thanks to a reduction of insulin motion in the brain.

Tschop Lab

Matthias Tschop (Institute of Diabetic issues and Being overweight Study, Munich) was one of the organizers of the meeting.  He operates a mega-lab in Germany and is the director of a analysis institute.  We have collaborated with him on comprehension the role of hypothalamic inflammatory signaling in obesity.  The most fascinating element of his talk was his description of obesity drugs he has developed by fusing gastrointestinal satiety hormones (like glucagon, GLP-1 and PYY) to one particular an additional in a one molecule.  He is essentially attempting to generate a drug that mimics the hormonal outcomes of gastric bypass, so that individuals can get the exact same fat loss and glucose handle rewards without surgical treatment.  His outcomes in rodents are amazing, and there are some preliminary knowledge suggesting a related effect in human beings.

Schwartz Lab

Mike Schwartz (my current mentor University of Washington) gave a great closing keynote handle.  He argued for a new framework for contemplating about blood glucose regulation.

Researchers have lengthy known that there are seemingly two techniques that blood glucose is controlled adhering to a food: 1) insulin raises tissue glucose uptake and lowers glucose creation by the liver, and 2) an additional unidentified system of glucose disposal that does not depend on insulin.  The latter is referred to as 'glucose effectiveness' and accounts for ~fifty% of the body's capability to regulate blood glucose adhering to a food!  Originally, glucose performance was imagined to be a passive, unregulated procedure.

One particular of the most intriguing current discoveries in diabetic issues analysis is that below certain conditions, the mind can entirely regulate blood glucose without any support from insulin.  This has been demonstrated several occasions in variety 1 diabetic rats that entirely absence insulin.  Infusing leptin into the mind of these animals virtually fully normalizes their blood glucose handle, the two by lowering liver glucose production and growing tissue glucose uptake.  My colleague Greg Morton has done a lot of the perform on this.  This indicates that the brain can have a significant impact on blood glucose manage, and that this system is possibly partially redundant with the insulin technique of blood glucose regulation (which is naturally extremely crucial beneath standard situation).

Dr. Schwartz introduced data suggesting that glucose efficiency might in fact be a controlled (not passive) process that final results at the very least in part from gastrointestinal signals acting on the mind, and that it is impaired in being overweight.  This has huge implications for diabetes treatment method, simply because if we can determine out how this method works, it may possibly pave the way for diabetic issues treatment options that never depend on insulin at all!  Most current drug therapies depend on insulin, insulin sensitizers, and/or insulin secretogogues.  Insulin treatment can have critical unwanted aspect consequences this sort of as hypoglycemia.

My Poster

I offered a poster on our obtaining that when rats are fed a fattening diet regime, they experience a quick enhance of activated caspase-3 in astrocytes of the arcuate nucleus and other brain regions (in 3 days).  Although rats obtained fat quickly on this diet plan, unwanted fat acquire did not show up to make clear the impact.  Caspase-three is normally associated with a variety of mobile loss of life known as apoptosis, nevertheless in this situation there was no apoptosis to be found.  We consider that caspase-three is element of the fast cellular injury response to this diet program that we noted formerly (

Title: Neuronal Control of Appetite, Metabolism and Weight
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