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Highlights from the Literature

Edited by Christopher D. Verrico

Nominated by Michael Caplan
Yale University School of Medicine
michael.caplan{at}yale.edu

Question: Does hypothalamic neurogenesis contribute to the sustained weight loss that occurs following ciliary neurotrophic factor (CNTF) administration?

Background: Recently CNTF, a protein that promotes neural stem cell survival and proliferation, was serendipitously found to induce and maintain weight loss in humans and mice even after cessation of treatment. A related compound, Axokine, initially showed promise in clinical trials as a weight loss drug, but patients eventually stopped responding and clinical trials were halted. Nonetheless, because CNTF activates signaling cascades in appetite-control centers of the brain (hypothalamic nuclei) and has neuroproliferative potential, Kokoeva et al. hypothesized that the persistent effect of CNTF on body weight regulation involves neurogenesis in the hypothalamus.

Observations: Mice were fed a high-fat diet for 2 months and then treated with CNTF and a marker of cell proliferation for 1 week. Two weeks later, CNTF was determined to induce cell proliferation in the hypothalamus, which expressed CNTF receptors and displayed phenotypes associated with controlling energy balance. In another experiment, cell proliferation was pharmacologically inhibited. Although these mice still lost weight during CNTF exposure, they regained the weight after discontinuing CNTF treatments. Similarly, they reported that leptin knockout mice also lost weight during CNTF treatment but regained the weight afterward.

Significance: These data suggest that hypothalamic neurogenesis underlies the sustained weight loss following CNTF treatment, which appears to be dependent on leptin signaling circuitry. Perhaps more intriguing, however, is that these results support the concept that physiologically relevant neurogenesis can occur in the hypothalamus of adult brains.

Nominated by Michael Caplan
Yale University School of Medicine
michael.caplan{at}yale.edu

Question: Are neuropeptide Y/agouti-related protein (NPY/AgRP) neurons essential for feeding?

Background: The arcuate nucleus of the hypothalamus contains NPY/AgRP and pro-opiomelanocortin (POMC) neurons, which are thought to play fundamental roles in regulating food intake and body weight. The evidence is clear for POMC neurons because mutating them, or their signaling pathways, leads to obesity in mice. Paradoxically, however, while intracranial administration of either NPY or AgRP stimulates feeding, mutating either of these genes or various NPY receptors only minimally impacts feeding.

Observations: Luquet et al. used an ingenious approach that allowed them to temporally control the ablation of NPY/AgRP neurons. As such, they found that when the ablation was induced in 1-day-old mice, body weight was only slightly affected, while feeding was largely unaffected. In stark contrast, when the ablation was induced in adult mice, there was a decrease in body weight and concomitant reduction in food intake that led to starvation. In an effort to characterize the compensatory mechanism observed in the neonates, some mice were ablated as neonates and then again as adults. In these experiments most of the mice survived, although some did die of starvation.

Significance: These remarkable results suggest that some form of compensatory adaptation occurs in neonates when NPY/AgRP neurons are ablated. In contrast, however, these neurons are essential for adult mice to survive. While the means by which this adaptation occurs is unclear, it is unlikely a result of enhanced functioning of residual NPY/AgRP neurons or the appearance of nascent NPY/AgRP neurons following the ablation. We now have a better understanding why previous attempts to impact feeding by mutating these genes were unsuccessful.

Point-Counterpoint series in Journal of Applied Physiology: Positive effects of intermittent hypoxia (live high:train low) on exercise performance are/are not mediated primarily by augmented red cell volume.

Nominated by Jerry Dempsey
Editor, Journal of Applied Physiology
University of Wisconsin-Madison
jdempsey{at}wisc.edu

Question: What mediates the improvement in performance following prolonged training under hypoxic conditions?

Background: Living high and training low (LHTL) is the phenomenon by which training at elevated altitudes for prolonged periods results in adaptive changes and thus improved aerobic performance at sea level. However, the mechanism responsible for the performance enhancement (improvement of Vo2max) is intensely debated. Levine and Stray-Gundersen posit that the improvement in performance is dependent on the length of exposure and results from an increase in red cell volume (RCV). In contrast, Gore and Hopkins argue that because none of the studies that describe changes in endurance performance following hypoxia were performed blind, the changes could be placebo effects and that the underlying cause is still unknown.

Observations: Levine and Stray-Gundersen first reported that LHTL increased RCV, Vo2max, and improved athletic performance while a control group that underwent identical training at sea level did not. They went on to show that when the LHTL group was divided, based on performance, into responders (improvements greater than the group mean) and nonresponders, the responders had a greater and more prolonged increase in RCV than nonresponders. Finally, they posit the fact that Vo2max can be affected by altering RCV independently of changes in altitude further supports their contention. Conversely, Gore and Hopkins contend that the increase in RCV reported by Levine and Stray-Gundersen and others are proportional to measurement errors. They cite studies, including their own, that use a different method to measure hemoglobin mass with a measurement error of ~2%, which reveal "little or no real change" in RCV. While they grant that changes in RCV may in fact be the mechanism in some studies whereby LHTL enhances performance, they argue that available data are insufficient to definitively conclude the mechanism of LHTL-induced performance enhancement. In fact, they suggest that an enhancement in oxygen utilization (i.e., exercise economy) could mediate the performance gains.

Significance: Levine and Stray-Gundersen refute the case by Gore and Hopkins that measurement error is an issue, and they cite the inconsistency of reports on improved exercise economy mediating performance enhancement. Gore and Hopkins accept that the role of exercise economy is unclear. However, they counter that this is also the case for the role of RCV. Sagaciously, Gore and Hopkins conclude with the notion that more research is necessary to definitively determine the contributions of these factors to the enhancement of performance gained by living high and training low.

Nominated by Michael Evans
Keele University, Staffordshire, UK
m.g.evans{at}cns.keele.ac.uk

Question: Is Ca²⁺ release from intracellular stores necessary for large-conductance voltage- and Ca²⁺-activated K⁺ (BK) channel activation in mammalian inner hair cells (IHCs)?

Background: BK channels of auditory IHCs provide negative feedback on cellular excitability and are theorized to open only when there is a coincident influx of Ca²⁺ and membrane depolarization. This is based on the fact that nonmammalian hair cell BK channels are colocalized with, and functionally coupled to, voltage-gated Ca²⁺ (Cav) channels from which extracellular Ca²⁺ enters the cell. However, although mammalian IHCs exhibit a fast, outward K⁺ current (I_K,f), which is thought to be mediated by BK channels, this current is unaffected by the removal of extracellular Ca²⁺. It has therefore been hypothesized that release from an intracellular voltage-dependent Ca²⁺ store modulates their activity.

Observations: Thurm et al. utilized patch-clamp recordings to elucidate the gating mechanism of BK channels in mammalian IHCs. They first determined that when the pore-forming -subunits of BK channels were specifically deleted, I_K,f was abolished. Subsequently, they found that the BK channels behaved predictably to increased intracellular Ca²⁺, although they were also unexpectedly activated in the absence of increased intracellular Ca²⁺.

Significance: These studies suggest that the mammalian BK channels mediate the I_K,f. However, this current occurred independently of increases in extracellular and/or intracellular Ca²⁺, which implies that unlike nonmammalian hair cell BK channels, functional coupling between BK and Cav channels does not exist. Although it is necessary to confirm these findings in vivo, the authors make the novel conclusion that the BK current in mammalian IHCs may be purely voltage-gated under physiological conditions, which could have relevance for understanding hearing impairments involving BK channels.

Nominated by David Gadsby
Associate Editor, Journal of General Physiology
Rockefeller University gadsby{at}mail.rockefeller.edu

Question: Is there an intracellular proton acceptor site in the prokaryotic CLC-type Cl^–/H⁺ exchanger?

Background: Recently, Accardi and Miller demonstrated that the molecular family of CLC-type Cl^– channels contains isoforms of two mechanistically different types. The prokaryotic homolog (ClC-ec1) was found to move Cl^– ions across the membrane by stoichiometric exchange for protons; i.e. function as a secondary active transporter and not a channel. Little is known about the mechanism by which the CLC protein couples Cl^– to H⁺ movement except that it is dependent on an extracellular-facing glutamate residue as mutations at E148 weaken H⁺ transport. Thus, Accardi et al. hypothesized that an analogous intracellular acceptor site exists to complete the transfer of the proton.

Observations: A systematic search for the inward-facing site involved mutating carboxyl-bearing residues. The scan identified a glutamate residue, E203, which is near the intracellular side, as the internal proton transfer site. While other mutations (E202 and D278) lowered H⁺ coupling to Cl^– transport, only the E203 mutation fully eradicated it.

Significance: These revolutionary data have implications for numerous diseases that result from disruption of CLC channel genes, as they suggest substrate exchange by ClC-ec1 is bifurcated. While Cl^– and H⁺ permeation pathways overlap at the extracellular side (E148), their paths appear to diverge as they move intracellularly because E203 is not in close proximity with the intracellular Cl^– site. Finally, because mutating either proton transfer residue (E148 or E203) does not significantly impact Cl^– transport, the CLC transporter mechanism is posited to be unconventional, but eerily reminiscent of how ion channels function.

Nominated by Pontus Persson
Editor, AJP-Regulatory, Integrative and Comparative Physiology
Humboldt University
pontus.persson{at}charite.de

Question: What underlies the inability of several labs to reproduce the appetite-suppressing effects of peptide YY(3–36) [PYY(3–36)]?

Background: Various gastrointestinal hormones play important roles in conveying information to the brain about the quantity and quality of food consumed during a meal. One such hormone, PYY(3–36), is postprandially released to regulate short-term food intake. PYY(3–36) was first reported to reduce hunger when injected into the abdominal cavity of rodents and thus thought to be a potential treatment for obesity. Since then however, several laboratories have failed to reproduce these results.

Observations: Chelikani et al. determined the effects of two different daily patterns of intravenous infusions of PYY(3–36) on food intake, body weight, and adiposity in rats with chronic indwelling cannulas. Rats received daily PYY(3–36) by intravenous infusions either over 3 hours, with 3 hours between infusions, or over 1 hour, every other hour. PYY(3–36) produced a sustained decrease in food intake, body weight gain, and adiposity but only when the intervals between administrations were 1 hour. There was a rapid onset and cessation to the anorexic responses with no significant desensitization.

Significance: These results suggest that PYY(3–36) decreases body weight and adiposity by reducing the size of meals and simultaneously increasing the satiation effects produced by meals. This highlights the importance of dosage patterns for producing a sustained effect of PYY(3–36) and implies that compensatory hyperphagia, but not tolerance, was responsible for the inability of other researchers to document these results. While there is still much to be determined about PYY(3–36), its therapeutic potential as an anti-obesity agent is restored.

Nominated by Jeff Sands
Editor, AJP-Renal Physiology
Emory University School of Medicine
jsands{at}emory.edu

Question: Does fructose-induced hyperuricemia have a role in the physiological perturbations associated with the metabolic syndrome?

Background: A sweetener found in many foods, fructose is a monosaccharide linked with obesity and diabetes. Fructose is distinct from glucose because it raises serum uric acid levels, thereby inhibiting the bioavailability of nitric oxide, which is a prerequisite for insulin to stimulate glucose uptake. Thus, Johnson and colleagues hypothesized that fructose-induced hyperuricemia plays a role in the pathogenesis of the metabolic syndrome.

Observations: A diet rich in fructose, but not a dextrose-rich diet, was found to cause hyperinsulinemia, hyper-triglyceridemia, and hyperuricemia in rats. However, these features of the metabolic syndrome were prevented when a pharmacological agent that lowers uric acid levels was coadministered with the fructose diet. Similarly, in rats already exposed to the high-fructose diet and, thus, which had already developed the metabolic syndrome, these features were mitigated by pharmacologically lower uric acid levels. In vitro studies were done to elucidate a possible mechanism by which hyperuricemia causes the metabolic syndrome; uric acid inhibited endothelial function, a hallmark of the metabolic syndrome.

Significance: Collectively, these data provide preclinical evidence that the pathogenesis of the fructose-induced metabolic syndrome may be caused by uric acid-induced endothelial dysfunction. This suggests that in contrast to some hypothesizes hyperuricemia may have a role in, and not be a mere consequence of, insulin resistance. Thus, as posited, the worldwide obesity and metabolic syndrome epidemics may result from fructose-induced hyperuricemia.

Nominated by Michael Welsh
University of Iowa College of Medicine
michael-welsh{at}uiowa.edu

Question: Does klotho affect Ca²⁺ reabsorption by the transient receptor potential (TRP) ion channel, TRPV5?

Background: TRPV5 was recently determined to mediate Ca²⁺ homeostasis in kidney epithelia. Klotho is a membrane glycoprotein that is highly expressed in kidney, but its function and downstream targets are unknown. However, several lines of evidence suggest that TRPV5 and klotho may be functionally linked: expression of both TRPV5 and klotho is controlled by vitamin D; TRPV5 knockouts have reduced klotho expression in kidneys; mice lacking TRPV5 or klotho display dysfunctions in balancing Ca²⁺ and metabolizing vitamin D. Thus, TRPV5 was hypothesized to be a downstream target of klotho.

Observations: TRPV5 and klotho were determined by Chang et al. to be colocalized in mouse kidney cells. In vitro experiments established that TRPV5-mediated Ca²⁺ influx was augmented by cotransfection with klotho or when TRPV5-transfected cells were exposed to supernatant from klotho-expressing cells. Further experiments suggest that the stimulatory action of klotho results from glycosylation of TRPV5, which induces TRPV5 accumulation in the plasma membrane.

Significance: The interaction between klotho and TRPV5 provides a previously unappreciated mechanism to control Ca²⁺ homeostasis and represents another major breakthrough by Hoenderop and colleagues in characterizing Ca²⁺ ion homeostasis in epithelia. These findings have widespread implications on understanding the aging process as klotho gene manipulations in mice have definitive effects on aging and the pathophysiology of several age-associated disorders are linked to Ca²⁺ abnormalities.

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