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Neuronal Command Of Appetite, Metabolism Too Weight

Last week, I attended a Keystone conference, "Neuronal Control of Appetite, Metabolism in addition to Weight", inwards Banff.  Keystone conferences are small, focused meetings that tend to attract high lineament science.  This special conference centered some my ain professional person enquiry interests, in addition to it was incredibly informative.  This postal service is a summary of some of the most salient points.

Rapid Pace of Scientific Progress


The coming together actually underscored the incredible touchstone of scientific progress on feeding, trunk weight in addition to metabolism, in addition to the key role the encephalon plays inwards these processes.  This is largely due to remarkable technical breakthroughs beingness applied past times people who know how to utilization them to response of import questions.  Conditional knockout in addition to transgenic mice, inwards which genes tin dismiss move manipulated inwards specific prison theater cellular telephone types, move on to play an of import role inwards neuroscience research.  However, the to a greater extent than recent introduction of optogenetic in addition to DREADD technology scientific discipline has been a quantum leap.  Optogenetics (light-activated ion channels) allows researchers to manipulate specific neuron populations using light, which offers exquisite spatial in addition to temporal control.  This is of import because  1) y'all tin dismiss burn (or inhibit) neurons inwards a agency that roughly approximates how they would burn naturally, in addition to 2) fifty-fifty inside tiny sub-nuclei of your brain, at that spot tin dismiss move a number of unlike prison theater cellular telephone types performing unlike functions, so having a technique amongst prison theater cellular telephone type specificity is useful (in contrast, imagine trying to create upward one's postulate heed the share of a nucleus past times lesioning it, which mightiness destroy 10 unlike intermingled prison theater cellular telephone populations all doing unlike things).  One early on representative of the application of optogenetics to feeding showed that activating AgRP neurons inwards the arcuate nucleus "evokes voracious feeding inside minutes" (1).  AgRP neurons were already known to move an of import neuron population for hunger in addition to feeding, but this experiment demonstrated it inwards the most convincing agency to date.

DREADD channels are used to activate or inhibit neuron activity using injections of the synthetic ligand CNO.  This is a squeamish technique because it's non-invasive (as opposed to optogenetics).  DREADD technology scientific discipline has bolstered the finding that activating AgRP neurons drives feeding in addition to rapid fatty gain (2).

There are a number of other interesting emerging technologies, but those 2 stand upward out.

Palmiter Lab

Richard Palmiter (University of Washington) gave the opening keynote address, describing his enquiry on a feeding circuit from AgRP neurons inwards the arcuate nucleus to the parabrachial nucleus in addition to so the key nucleus of the amygdala.  This circuit seems to close off nutrient intake inwards response to aversive stimuli (sickness, pain, fear), but may non play much of a role inwards feeding nether normal circumstances.

physician Palmiter too presented the remarkable finding that ablating AgRP neurons reverses the obesity in addition to infertility phenotype of ob/ob (leptin-deficient in addition to genetically obese) mice.

As the inventor of the transgenic mouse, physician Palmiter has played a major role inwards advancing scientific progress inwards the biological sciences.

Ozcan Lab

Umut Ozcan (Harvard University) presented information from his lab suggesting that leptin resistance inwards the hypothalamus is caused past times endoplasmic reticulum stress (ER stress; a assort of cellular stress that tin dismiss move caused past times misfolded proteins).  He has applied a chemical compound (SR-01) inwards obese mice that reduces ER stress, restores leptin sensitivity in addition to causes remarkable fatty loss.  This chemical compound has no trial inwards genetically obese mice that lack leptin receptors, in addition to it has no trial on lean mice, both of which back upward his hypothesis that it specifically increases leptin sensitivity inwards diet-induced obese mice.  He has been presenting these information at meetings for going on 2 years in addition to they haven't been published yet, which I abide by puzzling.  But they sure practice hold back promising.

Lam Lab

Tony Lam (University of Toronto) presented his information on the role of glucagon inwards blood glucose command via the brain.  Glucagon is an of import musician inwards blood glucose command via the liver, but its effects were by in addition to large assumed to termination from straight actions on the liver until physician Lam's findings.  He showed that glucagon too acts inwards the encephalon to regulate blood glucose, but inwards the opposite administration to its actions inwards the liver (suppresses blood glucose), in addition to that diet-induced obese animals lose the powerfulness to activate this mechanism, potentially contributing to elevated blood glucose inwards obesity.

Lowell Lab

Brad Lowell gave a remarkable talk.  His lab is focused on agreement how AgRP in addition to POMC neurons are regulated past times other neurons.  As stated above, this modest population of neurons inwards the arcuate nucleus is the most strong feeding circuit known inwards the brain.  POMC neurons are a well-characterized neuron population inwards the arcuate nucleus that suppress feeding.  The Lowell lab uses a combination of neuron tracing techniques (tracing the brain's wiring diagrams), optogenetics, in addition to electrophysiology (measuring the 'electrical' activity of neurons), to keen effect.

I won't move through the entire talk, which was incredibly information-dense, but I volition advert 2 key findings:

  1. What neurons activate AgRP neurons in addition to crusade hunger in addition to feeding?  PACAP in addition to TRH eurons inwards the paraventricular nucleus ship excitatory projections to AgRP neurons, in addition to stimulating these neurons greatly increases feeding.  The DMH too sends excitatory projections to AgRP neurons, but these are weaker.  
  2. The arcuate nucleus mediates a large share of leptin activeness on appetite in addition to trunk weight, yet deleting leptin receptors from arcuate neurons doesn't crusade much obesity, implying that they are receiving leptin-responsive signals from upstream neurons.  What are these neurons?  Dr. Lowell showed that leptin receptor expressing neurons inwards the dorsomedial hypothalamus ship dense inhibitory projections to AgRP neurons.  Activating these DMH neurons potently suppresses feeding.

Sternson Lab

Scott Sternson (NIH's prestigious Janelia farm campus) is interested inwards the downstream targets of AgRP neurons, in addition to he too makes extensive utilization of optogenetics, DREADDs in addition to related approaches.  Dr. Sternson argued for a prototype shift inwards agreement feeding-related motivation.  Activating AgRP neurons increases motivation for food, in all probability reflecting hunger.  But what is hunger, in addition to how does it shape hereafter nutrient pick behaviors (via vantage processes)?  He presented information suggesting that hunger drives nutrient intake demeanor in addition to learning through a procedure involving negative reinforcement.

He showed that activating AgRP neurons inwards mice (presumably inducing a hunger-like state) is aversive (unpleasant).  Also, experimentally suppressing the activation of AgRP neurons caused past times hunger is reinforcing/rewarding (increases the likelihood of seeking situations/flavors associated amongst the cessation of AgRP neuron activity), basically suggesting that the satiety state is reinforcing because it relieves the unpleasant state of hunger.  So animals larn to prefer situations associated amongst the relieving of the aversive 'hunger' state, in addition to this is share of how the vantage organization learns how to guide food-seeking behavior

Zeltser Lab

Lori Zeltser (Columbia University) had a fascinating beak on anorexia that too contained a real interesting tibit on insulin in addition to obesity.  I won't acquire into all the details of her talk, but she is researching the intersection betwixt genes, calorie restriction, in addition to psychological stress inwards promoting anorexia.

The Val66Met allele of the BDNF cistron is strongly associated amongst anorexia inwards at to the lowest degree some human studies.  BDNF is share of the leptin signaling pathway in addition to thus plays an of import role inwards the command of nutrient intake in addition to trunk fatness.  BDNF Val66Met mice are relatively normal, but when stressed (by social isolation) or temporarily calorie-restricted, mice volition move through spontaneous periods of aphagia (no eating).  I abide by it remarkable that it's possible to model anorexia inwards mice, but her information were fairly convincing that this human genetic susceptibility constituent increases the postulate chances of anorexia nether weather of psychological or metabolic stress.  We don't know if the same is truthful inwards humans, but it seems plausible based on her data.

She presented some other interesting tidbit that's relevant to the insulin-obesity idea: mice amongst a hypothalamus-specific deletion (Nkx2.1) of the insulin receptor have got normal trunk weight, trunk fatness, in addition to leptin levels.  The implication is that (complete) insulin resistance inwards the hypothalamus does non atomic number 82 to leptin resistance or obesity, which bears on i of the to a greater extent than pop versions of the insulin-obesity hypothesis (e.g., the thought that hyperinsulinemia causes hypothalamic insulin resistance, which causes hypothalamic leptin resistance, which leads to obesity).

Cowley Lab

Michael Cowley (Monash University) gave i of the most fascinating talks, partially because I wasn't aware of this draw of piece of job of investigation prior to the conference.  In short, he has shown that elevated leptin is largely responsible for obesity-induced hypertension (high blood pressure) inwards rodents, in addition to the prove suggests the same is truthful for humans, who too tend to educate hypertension amongst obesity.  He (with Stephanie Simonds) of late wrote an fantabulous review article inwards Trends inwards Neurosciences that covers most of the prove (3).  The illustrations of the sympathetic (SNS) in addition to parasympathetic (PNS) nervous systems, in addition to the encephalon regions involved inwards SNS in addition to PNS natural springtime are actually outstanding inwards that paper.  I'll move hanging on to it equally a reference.

The encephalon controls the SNS in addition to PNS, which regulates many 'autonomic' (unconscious) functions similar pump rate, lipolysis, glucose control, adrenaline release, estrus production, digestion, in addition to blood pressure.  Normally, it does so inwards response to leptin in addition to other peripheral signals.  During the evolution of obesity, the encephalon becomes resistant to many of leptin's actions, such equally its powerfulness to suppress nutrient intake in addition to trim back trunk fatness.  However, it doesn't move resistant to leptin's powerfulness to stimulate the SNS, so the SNS goes into overdrive inwards obese rodents in addition to humans.  Dr. Cowley's information advise that this is due inwards large share to increased leptin acting inwards the dorsomedial hypothalamus.

Insulin too activates the SNS, in addition to obesity is too associated amongst elevated insulin.  Elevated insulin acting on the encephalon is too in all probability a constituent that contributes to hypertension through similar pathways.  Interestingly, low-carbohydrate diets oftentimes have got a dramatic trial to speedily trim back blood pressure.  Dr. Cowley's results advise that this is in all probability due to a reduction of insulin activeness inwards the brain.

Tschop Lab

Matthias Tschop (Institute of Diabetes in addition to Obesity Research, Munich) was i of the organizers of the conference.  He runs a mega-lab inwards Deutschland in addition to is the manager of a enquiry institute.  We have got collaborated amongst him on agreement the role of hypothalamic inflammatory signaling inwards obesity.  The most interesting share of his beak was his description of obesity drugs he has created past times fusing gastrointestinal satiety hormones (including glucagon, GLP-1 in addition to PYY) to i some other inwards a unmarried molecule.  He is basically trying to create a drug that mimics the hormonal effects of gastric bypass, so that people tin dismiss acquire the same weight loss in addition to glucose command benefits without surgery.  His results inwards rodents are impressive, in addition to at that spot are some preliminary information suggesting a similar trial inwards humans.

Schwartz Lab

Mike Schwartz (my electrical flow mentor; University of Washington) gave a keen closing keynote address.  He argued for a novel framework for thinking nearly blood glucose regulation.

Researchers have got long known that at that spot are apparently 2 ways that blood glucose is regulated next a meal: 1) insulin increases tissue glucose uptake in addition to reduces glucose production past times the liver, in addition to 2) some other unknown machinery of glucose disposal that does non rely on insulin.  The latter is referred to equally 'glucose effectiveness' in addition to accounts for 50% of the body's powerfulness to regulate blood glucose next a meal!  Originally, glucose effectiveness was thought to move a passive, unregulated process.

One of the most interesting recent discoveries inwards diabetes enquiry is that nether sure conditions, the encephalon tin dismiss completely regulate blood glucose without whatever assistance from insulin.  This has been shown multiple times inwards type 1 diabetic rats that completely lack insulin.  Infusing leptin into the encephalon of these animals almost completely normalizes their blood glucose control, both past times reducing liver glucose production in addition to increasing tissue glucose uptake.  My colleague Greg Morton has done a lot of the piece of job on this.  This suggests that the encephalon tin dismiss have got a major influence on blood glucose control, in addition to that this organization is in all probability partially redundant amongst the insulin organization of blood glucose rule (which is patently real of import nether normal circumstances).

physician Schwartz presented information suggesting that glucose effectiveness may inwards fact move a regulated (not passive) procedure that results at to the lowest degree inwards share from gastrointestinal signals acting on the brain, in addition to that it is impaired inwards obesity.  This has huge implications for diabetes treatment, because if nosotros tin dismiss figure out how this procedure works, it may pave the agency for diabetes treatments that don't rely on insulin at all!  Most electrical flow drug treatments rely on insulin, insulin sensitizers, and/or insulin secretogogues.  Insulin therapy tin dismiss have got serious unwanted side effects such equally hypoglycemia.

My Poster

I presented a poster on our finding that when rats are fed a fattening diet, they sense a rapid increment of activated caspase-3 inwards astrocytes of the arcuate nucleus in addition to other encephalon regions (within iii days).  Although rats gained fatty speedily on this diet, fatty gain did non seem to explicate the effect.  Caspase-3 is usually associated amongst a type of prison theater cellular telephone expiry called apoptosis, yet inwards this instance at that spot was no apoptosis to move found.  We cry upward that caspase-3 is share of the rapid cellular injury response to this diet that nosotros reported previously (4).  This suggests a novel non-apoptotic role for caspase-3 inwards the brain's response to injury, in addition to suggests that astrocytes may move trying to incorporate harm to of import feeding centers early on during exposure to a fattening diet.  The poster was good received.  These information were accepted for publication inwards the journal Brain Research 2 weeks ago.

Conclusion

The conference was fantabulous in addition to left my postulate heed extremely full.  There were many informative talks in addition to posters that I left out of this summary.  The touchstone of scientific regain correct right away is mind-boggling; it would move a full-time chore simply to hold upward amongst electrical flow findings inwards my plain alone.  I'm confident that this novel enquiry volition pay dividends inwards agreement in addition to improving human health, in addition to peculiarly preventing in addition to treating obesity in addition to diabetes.  In the meantime, nosotros already know how to foreclose (and to a lesser extent, treat) most obesity in addition to diabetes using diet in addition to lifestyle.


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