Publications by authors named "Kamal Rahmouni"

150 Publications

Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension.

Cell Metab 2021 Apr 30. Epub 2021 Apr 30.

Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Medizinische Klinik and Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany. Electronic address:

Pathologies of the micro- and macrovascular systems are a hallmark of the metabolic syndrome, which can lead to chronically elevated blood pressure. However, the underlying pathomechanisms involved still need to be clarified. Here, we report that an obesity-associated increase in serum leptin triggers the select expansion of the micro-angioarchitecture in pre-autonomic brain centers that regulate hemodynamic homeostasis. By using a series of cell- and region-specific loss- and gain-of-function models, we show that this pathophysiological process depends on hypothalamic astroglial hypoxia-inducible factor 1α-vascular endothelial growth factor (HIF1α-VEGF) signaling downstream of leptin signaling. Importantly, several distinct models of HIF1α-VEGF pathway disruption in astrocytes are protected not only from obesity-induced hypothalamic angiopathy but also from sympathetic hyperactivity or arterial hypertension. These results suggest that hyperleptinemia promotes obesity-induced hypertension via a HIF1α-VEGF signaling cascade in hypothalamic astrocytes while establishing a novel mechanistic link that connects hypothalamic micro-angioarchitecture with control over systemic blood pressure.
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http://dx.doi.org/10.1016/j.cmet.2021.04.007DOI Listing
April 2021

OPA1 deletion in brown adipose tissue Improves thermoregulation and systemic metabolism via FGF21.

Elife 2021 May 4;10. Epub 2021 May 4.

Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, University of Iowa, Iowa City, United States.

Adrenergic stimulation of brown adipocytes alters mitochondrial dynamics, including the mitochondrial fusion protein optic atrophy 1 (OPA1). However, direct mechanisms linking OPA1 to brown adipose tissue (BAT) physiology are incompletely understood. We utilized a mouse model of selective OPA1 deletion in BAT (OPA1 BAT KO) to investigate the role of OPA1 in thermogenesis. OPA1 is required for cold-induced activation of thermogenic genes in BAT. Unexpectedly, OPA1 deficiency induced fibroblast growth factor 21 (FGF21) as a BATokine in an activating transcription factor 4 (ATF4)-dependent manner. BAT-derived FGF21 mediates an adaptive response, by inducing browning of white adipose tissue, increasing resting metabolic rates, and improving thermoregulation. However, mechanisms independent of FGF21, but dependent on ATF4 induction, promote resistance to diet-induced obesity in OPA1 BAT KO mice. These findings uncover a homeostatic mechanism of BAT-mediated metabolic protection governed in part by an ATF4-FGF21 axis, that is activated independently of BAT thermogenic function.
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http://dx.doi.org/10.7554/eLife.66519DOI Listing
May 2021

Counterpoint regarding an alternative hypothesis for why exposure to static magnetic and electric fields treat type 2 diabetes.

Am J Physiol Endocrinol Metab 2021 Apr 12. Epub 2021 Apr 12.

Radiation Oncology, Univerisity of Iowa.

Petersen et al. hypothesize that vestibular stress underlies the therapeutic effects of static magnetic and electric fields in type 2 diabetes. However, our experimental data directly contradict the predictions made by this alternative hypothesis. Here, we discuss key findings that support a mechanism that is independent of vestibular stress to explain the remarkable insulin sensitizing effects of static magnetic and electric fields. Our findings are consistent with a redox-dependent mechanism that involves mitochondrial oxidants in liver and the induction of an insulin sensitizing redox response.
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http://dx.doi.org/10.1152/ajpendo.00110.2021DOI Listing
April 2021

BBSome ablation in SF1 neurons causes obesity without comorbidities.

Mol Metab 2021 Mar 13;48:101211. Epub 2021 Mar 13.

Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Veterans Affairs Health Care System, Iowa City, IA, USA; Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Obesity Research and Education Initiative, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA. Electronic address:

Objectives: The hypothalamic ventromedial nucleus (VMH) plays a major role in metabolic control, but the molecular mechanisms involved remain poorly defined. We analyzed the relevance of the BBSome, a protein complex composed of 8 Bardet-Biedl syndrome (BBS) proteins including BBS1, in VMH steroidogenic factor 1 (SF1) neurons for the control of energy homeostasis and related physiological processes.

Methods: We generated mice bearing selective BBSome disruption, through Bbs1 gene deletion, in SF1 neurons (SF1/Bbs1). We analyzed the consequence on body weight, glucose homeostasis, and cardiovascular autonomic function of BBSome loss in SF1 neurons.

Results: SF1/Bbs1 mice had increased body weight and adiposity under normal chow conditions. Food intake, energy absorption, and digestive efficiency were not altered by Bbs1 gene deletion in SF1 neurons. SF1/Bbs1 mice exhibited lower energy expenditure, particularly during the dark cycle. Consistent with this finding, SF1/Bbs1 mice displayed reduced sympathetic nerve traffic and expression of markers of thermogenesis in brown adipose tissue. SF1/Bbs1 mice also had lower sympathetic nerve activity to subcutaneous white adipose tissue that was associated with a protein expression profile that promotes lipid accumulation. Notably, despite obesity and hyperinsulinemia, SF1/Bbs1 mice did not exhibit significant changes in glucose metabolism, insulin sensitivity, blood pressure, and baroreflex sensitivity.

Conclusions: Our findings demonstrate that the SF1 neuron BBSome is necessary for the regulation of energy homeostasis through modulation of the activity of the sympathetic nervous system and that the SF1 neuron BBSome is required for the development of obesity-related comorbidities.
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http://dx.doi.org/10.1016/j.molmet.2021.101211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065214PMC
March 2021

mTORC1 (Mechanistic Target of Rapamycin Complex 1) Signaling in Endothelial and Smooth Muscle Cells Is Required for Vascular Function.

Hypertension 2021 Feb 28;77(2):594-604. Epub 2020 Dec 28.

From the Department of Neuroscience and Pharmacology (J.J.R., D.-F.G., D.A.M., K.R.), University of Iowa Carver College of Medicine.

mTORC1 (Mechanistic target of rapamycin complex 1) serves as a molecular hub and intracellular energy sensor that regulate various cellular processes. Emerging evidence points to mTORC1 signaling as a critical regulator of cardiovascular function with implications for cardiovascular disease. Here, we show that selective disruption of mTORC1, through conditional gene deletion, in endothelial or smooth muscle cells alter vascular function. Endothelial cell-specific Raptor deletion results in reduced relaxation responses evoked by acetylcholine in the aorta but not in the mesenteric artery. Of note, endothelial-specific Raptor deletion did not affect endothelial-independent vasorelaxation nor the contractile responses of the aorta or mesenteric artery. Interestingly, endothelial Raptor haploinsufficiency did not alter vascular endothelial function but attenuated the endothelial dysfunction evoked by angiotensin II. Smooth muscle cell-specific conditional deletion of Raptor reduces both endothelial- and smooth muscle-dependent relaxation responses as well as receptor-dependent and -independent contractility in the aorta. This was associated with activation of autophagy signaling. Notably, the changes in vascular function evoked by endothelial and smooth muscle Raptor deletion were independent of changes in blood pressure and heart rate. Together, these data suggest that vascular mTORC1 signaling is a critical regulator of vascular endothelial and smooth muscle function. mTORC1 signaling may represent a potential target for the treatment of vascular diseases associated with altered mTORC1 activity.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14708DOI Listing
February 2021

Endocannabinoid Receptor-1 and Sympathetic Nervous System Mediate the Beneficial Metabolic Effects of Gastric Bypass.

Cell Rep 2020 10;33(4):108270

Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Orders of Eagles Diabetes Research Center, Iowa City, IA 52242, USA; Veterans Affairs Health Care System, Iowa City, IA 52242, USA; Obesity Research & Education Initiative, University of Iowa, Iowa City, IA 52242, USA. Electronic address:

The exact mechanisms underlying the metabolic effects of bariatric surgery remain unclear. Here, we demonstrate, using a combination of direct and indirect calorimetry, an increase in total resting metabolic rate (RMR) and specifically anaerobic RMR after Roux-en-Y gastric bypass (RYGB), but not sleeve gastrectomy (SG). We also show an RYGB-specific increase in splanchnic sympathetic nerve activity and "browning" of visceral mesenteric fat. Consequently, selective splanchnic denervation abolishes all beneficial metabolic outcomes of gastric bypass that involve changes in the endocannabinoid signaling within the small intestine. Furthermore, we demonstrate that administration of rimonabant, an endocannabinoid receptor-1 (CB1) inverse agonist, to obese mice mimics RYGB-specific effects on energy balance and splanchnic nerve activity. On the other hand, arachidonoylethanolamide (AEA), a CB1 agonist, attenuates the weight loss and metabolic signature of this procedure. These findings identify CB1 as a key player in energy regulation post-RYGB via a pathway involving the sympathetic nervous system.
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http://dx.doi.org/10.1016/j.celrep.2020.108270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660289PMC
October 2020

Hypothalamic MC4R regulates glucose homeostasis through adrenaline-mediated control of glucose reabsorption via renal GLUT2 in mice.

Diabetologia 2021 Jan 14;64(1):181-194. Epub 2020 Oct 14.

Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.

Aims/hypothesis: Melanocortin 4 receptor (MC4R) mutation is the most common cause of known monogenic obesity in humans. Unexpectedly, humans and rodents with MC4R deficiency do not develop hyperglycaemia despite chronic obesity and insulin resistance. To explain the underlying mechanisms for this phenotype, we determined the role of MC4R in glucose homeostasis in the presence and absence of obesity in mice.

Methods: We used global and hypothalamus-specific MC4R-deficient mice to investigate the brain regions that contribute to glucose homeostasis via MC4R. We performed oral, intraperitoneal and intravenous glucose tolerance tests in MC4R-deficient mice that were either obese or weight-matched to their littermate controls to define the role of MC4R in glucose regulation independently of changes in body weight. To identify the integrative pathways through which MC4R regulates glucose homeostasis, we measured renal and adrenal sympathetic nerve activity. We also evaluated glucose homeostasis in adrenaline (epinephrine)-deficient mice to investigate the role of adrenaline in mediating the effects of MC4R in glucose homeostasis. We employed a graded [C]glucose infusion procedure to quantify renal glucose reabsorption in MC4R-deficient mice. Finally, we measured the levels of renal glucose transporters in hypothalamus-specific MC4R-deficient mice and adrenaline-deficient mice using western blotting to ascertain the molecular mechanisms underlying MC4R control of glucose homeostasis.

Results: We found that obese and weight-matched MC4R-deficient mice exhibited improved glucose tolerance due to elevated glucosuria, not enhanced beta cell function. Moreover, MC4R deficiency selectively in the paraventricular nucleus of the hypothalamus (PVH) is responsible for reducing the renal threshold for glucose as measured by graded [C]glucose infusion technique. The MC4R deficiency suppressed renal sympathetic nerve activity by 50% in addition to decreasing circulating adrenaline and renal GLUT2 levels in mice, which contributed to the elevated glucosuria. We further report that adrenaline-deficient mice recapitulated the increased excretion of glucose in urine observed in the MC4R-deficient mice. Restoration of circulating adrenaline in both the MC4R- and adrenaline-deficient mice reversed their phenotype of improved glucose tolerance and elevated glucosuria, demonstrating the role of adrenaline in mediating the effects of MC4R on glucose reabsorption.

Conclusions/interpretation: These findings define a previously unrecognised function of hypothalamic MC4R in glucose reabsorption mediated by adrenaline and renal GLUT2. Taken together, our findings indicate that elevated glucosuria due to low sympathetic tone explains why MC4R deficiency does not cause hyperglycaemia despite inducing obesity and insulin resistance. Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05289-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718429PMC
January 2021

Exposure to Static Magnetic and Electric Fields Treats Type 2 Diabetes.

Cell Metab 2020 Oct;32(4):561-574.e7

Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa Hospitals & Clinics, Iowa City, IA, USA.

Aberrant redox signaling underlies the pathophysiology of many chronic metabolic diseases, including type 2 diabetes (T2D). Methodologies aimed at rebalancing systemic redox homeostasis have had limited success. A noninvasive, sustained approach would enable the long-term control of redox signaling for the treatment of T2D. We report that static magnetic and electric fields (sBE) noninvasively modulate the systemic GSH-to-GSSG redox couple to promote a healthier systemic redox environment that is reducing. Strikingly, when applied to mouse models of T2D, sBE rapidly ameliorates insulin resistance and glucose intolerance in as few as 3 days with no observed adverse effects. Scavenging paramagnetic byproducts of oxygen metabolism with SOD2 in hepatic mitochondria fully abolishes these insulin sensitizing effects, demonstrating that mitochondrial superoxide mediates induction of these therapeutic changes. Our findings introduce a remarkable redox-modulating phenomenon that exploits endogenous electromagneto-receptive mechanisms for the noninvasive treatment of T2D, and potentially other redox-related diseases.
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http://dx.doi.org/10.1016/j.cmet.2020.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819711PMC
October 2020

Nicotine' actions on energy balance: Friend or foe?

Pharmacol Ther 2021 Mar 26;219:107693. Epub 2020 Sep 26.

Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain. Electronic address:

Obesity has reached pandemic proportions and is associated with severe comorbidities, such as type 2 diabetes mellitus, hepatic and cardiovascular diseases, and certain cancer types. However, the therapeutic options to treat obesity are limited. Extensive epidemiological studies have shown a strong relationship between smoking and body weight, with non-smokers weighing more than smokers at any age. Increased body weight after smoking cessation is a major factor that interferes with their attempts to quit smoking. Numerous controlled studies in both humans and rodents have reported that nicotine, the main bioactive component of tobacco, exerts a marked anorectic action. Furthermore, nicotine is also known to modulate energy expenditure, by regulating the thermogenic activity of brown adipose tissue (BAT) and the browning of white adipose tissue (WAT), as well as glucose homeostasis. Many of these actions occur at central level, by controlling the activity of hypothalamic neuropeptide systems such as proopiomelanocortin (POMC), or energy sensors such as AMP-activated protein kinase (AMPK). However, direct impact of nicotine on metabolic tissues, such as BAT, WAT, liver and pancreas has also been described. Here, we review the actions of nicotine on energy balance. The relevance of this interaction is interesting, because considering the restricted efficiency of obesity treatments, a possible complementary approach may focus on compounds with known pharmacokinetic profile and pharmacological actions, such as nicotine or nicotinic acetylcholine receptors signaling.
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http://dx.doi.org/10.1016/j.pharmthera.2020.107693DOI Listing
March 2021

Activation of hypothalamic AgRP and POMC neurons evokes disparate sympathetic and cardiovascular responses.

Am J Physiol Heart Circ Physiol 2020 11 18;319(5):H1069-H1077. Epub 2020 Sep 18.

Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa.

The arcuate nucleus of the hypothalamus (ARC) plays a key role in linking peripheral metabolic status to the brain melanocortin system, which influences a wide range of physiological processes including the sympathetic nervous system and blood pressure. The importance of the activity of agouti-related peptide (AgRP)- and proopiomelanocortin (POMC)-expressing neurons, two molecularly distinct populations of ARC neurons, for metabolic regulation is well established, but their relevance for sympathetic and cardiovascular control remains unclear. We used designer receptors exclusively activated by designer drug (DREADD) technology to study how activation of AgRP and POMC neurons affect renal sympathetic nerve traffic and blood pressure. In addition to the drastic feeding-stimulatory effect, DREADD-mediated activation of AgRP, but not POMC neurons, induced an acute reduction in renal sympathetic nerve activity in conscious mice. Paradoxically, however, DREADD-mediated chronic activation of AgRP neurons caused a significant increase in blood pressure specifically in the inactive light phase. On the other hand, chronic activation of POMC neurons led to a significant reduction in blood pressure. These results bring new insights to a previously unappreciated role of ARC AgRP and POMC neuronal activity in autonomic and cardiovascular regulation. Agouti-related peptide (AgRP)- and proopiomelanocortin (POMC)-expressing neurons of the arcuate nucleus are essential components of the brain melanocortin system that controls various physiological processes. Here, we tested the metabolic and cardiovascular effects of direct activation of these two populations of neurons. Our findings show that, in addition to stimulation of food intake, chemogenetic mediated activation of hypothalamic arcuate nucleus AgRP, but not POMC, neurons reduce renal sympathetic traffic. Despite this, chronic activation of AgRP neurons increased blood pressure. However, chronic activation of POMC neurons led to a significant reduction in blood pressure. Our findings highlight the importance of arcuate nucleus AgRP and POMC neuronal activity in autonomic and cardiovascular regulation.
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http://dx.doi.org/10.1152/ajpheart.00411.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789969PMC
November 2020

A leptin-BDNF pathway regulating sympathetic innervation of adipose tissue.

Nature 2020 07 22;583(7818):839-844. Epub 2020 Jul 22.

Laboratory of Molecular Genetics, Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.

Mutations in the leptin gene (ob) result in a metabolic disorder that includes severe obesity, and defects in thermogenesis and lipolysis, both of which are adipose tissue functions regulated by the sympathetic nervous system. However, the basis of these sympathetic-associated abnormalities remains unclear. Furthermore, chronic leptin administration reverses these abnormalities in adipose tissue, but the underlying mechanism remains to be discovered. Here we report that ob/ob mice, as well as leptin-resistant diet-induced obese mice, show significant reductions of sympathetic innervation of subcutaneous white and brown adipose tissue. Chronic leptin treatment of ob/ob mice restores adipose tissue sympathetic innervation, which in turn is necessary to correct the associated functional defects. The effects of leptin on innervation are mediated via agouti-related peptide and pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus. Deletion of the gene encoding the leptin receptor in either population leads to reduced innervation in fat. These agouti-related peptide and pro-opiomelanocortin neurons act via brain-derived neurotropic factor-expressing neurons in the paraventricular nucleus of the hypothalamus (BDNF). Deletion of BDNF blunts the effects of leptin on innervation. These data show that leptin signalling regulates the plasticity of sympathetic architecture of adipose tissue via a top-down neural pathway that is crucial for energy homeostasis.
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http://dx.doi.org/10.1038/s41586-020-2527-yDOI Listing
July 2020

Increased Susceptibility of Mice Lacking Renin-b to Angiotensin II-Induced Organ Damage.

Hypertension 2020 08 8;76(2):468-477. Epub 2020 Jun 8.

From the Department of Physiology, Medical College of Wisconsin, Milwaukee (P.N., J.G., J.W., K.-T.L., J.L.G., C.D.S.).

Several cardiac and renal diseases are attributed to a dysregulation of the renin-angiotensin system. Renin, the rate-limiting enzyme of the renin-angiotensin system, has 2 isoforms. The classical renin isoform (renin-a) encoding preprorenin is mainly confined to the juxtaglomerular cells and released into the circulation upon stimulation. Alternatively, renin-b is predicted to remain intracellular and is expressed in the brain, heart, and adrenal gland. In the brain, ablation of renin-b (Ren-b mice) results in increased brain renin-angiotensin system activity. However, the consequences of renin-b ablation in tissues outside the brain remain unknown. Therefore, we hypothesized that renin-b protects from hypertensive cardiac and renal end-organ damage in mice. Ren-b mice exhibited normal blood pressure at baseline. Thus, we induced hypertension by using a slow pressor dose of Ang II (angiotensin II). Ang II increased blood pressure in both wild type and Ren-b to the same degree. Although the blood pressure between Ren-b and wild-type mice was elevated equally, 4-week infusion of Ang II resulted in exacerbated cardiac remodeling in Ren-b mice compared with wild type. Ren-b mice also exhibited a modest increase in renal glomerular matrix deposition, elevated plasma aldosterone, and a modestly enhanced dipsogenic response to Ang II. Interestingly, ablation of renin-b strongly suppressed plasma renin, but renal cortical renin mRNA was preserved. Altogether, these data indicate that renin-b might play a protective role in the heart, and thus renin-b could be a potential target to treat hypertensive heart disease.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347438PMC
August 2020

Single-Nucleus RNA Sequencing of the Hypothalamic Arcuate Nucleus of C57BL/6J Mice After Prolonged Diet-Induced Obesity.

Hypertension 2020 08 8;76(2):589-597. Epub 2020 Jun 8.

Department of Physiology (V.A.W., K.B., C.D.S., A.E.K., J.L.G.), Medical College of Wisconsin, Milwaukee.

Prolonged obesity is associated with blunted feeding and thermogenic autonomic responses to leptin, but cardiovascular responses to leptin are maintained. This state of selective leptin resistance is, therefore, proposed to contribute to the pathogenesis and maintenance of obesity-associated hypertension. Cells of the arcuate nucleus of the hypothalamus detect leptin, and although the cellular and molecular mechanisms remain unclear, altered arcuate nucleus biology is hypothesized to contribute to selective leptin resistance. Male C57BL/6J mice were fed a high-fat diet (HFD) or chow from 8 to 18 weeks of age, as this paradigm models selective leptin resistance. Nuclei were then isolated from arcuate nucleus for single-nucleus RNA sequencing. HFD caused expected gains in adiposity and circulating leptin. Twenty-three unique cell-type clusters were identified, and Ingenuity Pathway Analysis was used to explore changes in gene expression patterns due to chronic HFD within each cluster. Notably, gene expression signatures related to leptin signaling exhibited suppression predominantly in neurons identified as the Agouti-related peptide () subtype. Ingenuity Pathway Analysis results were also consistent with alterations in CREB (cAMP response element-binding protein) signaling in neurons after HFD, and reduced phosphorylated CREB was confirmed in arcuate nucleus after prolonged HFD by capillary electrophoresis-based Western blotting. These findings support the concept that prolonged HFD-induced obesity is associated with selective changes in neuron biology, possibly secondary to altered CREB signaling.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347451PMC
August 2020

Failure to vasodilate in response to salt loading blunts renal blood flow and causes salt-sensitive hypertension.

Cardiovasc Res 2021 Jan;117(1):308-319

Department of Physiology, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.

Aims: Salt-sensitive (SS) hypertension is accompanied by impaired vasodilation in the systemic and renal circulation. However, the causal relationship between vascular dysfunction and salt-induced hypertension remains controversial. We sought to determine whether primary vascular dysfunction, characterized by a failure to vasodilate during salt loading, plays a causal role in the pathogenesis of SS hypertension.

Methods And Results: Mice selectively expressing a peroxisome proliferator-activated receptor γ dominant-negative mutation in vascular smooth muscle (S-P467L) exhibited progressive SS hypertension during a 4 week high salt diet (HSD). This was associated with severely impaired vasodilation in systemic and renal vessels. Salt-induced impairment of vasodilation occurred as early as 3 days after HSD, which preceded the onset of SS hypertension. Notably, the overt salt-induced hypertension in S-P467L mice was not driven by higher cardiac output, implying elevations in peripheral vascular resistance. In keeping with this, HSD-fed S-P467L mice exhibited decreased smooth muscle responsiveness to nitric oxide (NO) in systemic vessels. HSD-fed S-P467L mice also exhibited elevated albuminuria and a blunted increase in urinary NO metabolites which was associated with blunted renal blood flow and increased sodium retention mediated by a lack of HSD-induced suppression of NKCC2. Blocking NKCC2 function prevented the salt-induced increase in blood pressure in S-P467L mice.

Conclusion: We conclude that failure to vasodilate in response to salt loading causes SS hypertension by restricting renal perfusion and reducing renal NO through a mechanism involving NKCC2 in a mouse model of vascular peroxisome proliferator-activated receptor γ impairment.
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http://dx.doi.org/10.1093/cvr/cvaa147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797211PMC
January 2021

Cardiovascular Regulation by the Neuronal BBSome.

Hypertension 2020 04 9;75(4):1082-1090. Epub 2020 Mar 9.

From the Department of Neuroscience and Pharmacology (D.-F.G., J.J.R., D.A.M., K.R.), University of Iowa Carver College of Medicine, Iowa City.

The BBSome, a complex of 8 BBS (Bardet-Biedl syndrome) proteins known for its role in the control of cilia function and other cellular processes, has been implicated in blood pressure control, but the underlying mechanisms are not fully understood. Here, we show that neuronal BBSome plays an important role in blood pressure regulation. Targeted inactivation of the BBSome in the nervous system through gene deletion causes sympathetically mediated increase in blood pressure in mice. This phenotype is reproduced by selective ablation of the gene from the LRb (leptin receptor)-expressing neurons. Strikingly, the well-known role of the BBSome in the regulation of cilia formation and function is unlikely to account for the prohypertensive effect of BBSome inactivation as disruption of the IFT (intraflagellar transport) machinery required for ciliogenesis by deleting the gene in LRb neurons had no effect on arterial pressure and sympathetic nerve activity. Furthermore, we found that gene deletion from AgRP (agouti-related protein) neurons or POMC (proopiomelanocortin) neurons increased renal and splanchnic sympathetic nerve activity without altering blood pressure. This lack of blood pressure increase despite the sympathetic overdrive may be explained by vascular adrenergic desensitization as indicated by the reduced vascular contractile response evoked by phenylephrine and the decreased expression of adrenergic receptors. Our results identify the neuronal BBSome as a new player in hemodynamic, sympathetic, and vascular regulation, in a manner independent of cilia.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101031PMC
April 2020

Liver-derived FGF21 is essential for full adaptation to ketogenic diet but does not regulate glucose homeostasis.

Endocrine 2020 01 14;67(1):95-108. Epub 2019 Nov 14.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.

Background: Fibroblast growth factor 21 (FGF21) is expressed in several metabolically active tissues, including liver, fat, and acinar pancreas, and has pleiotropic effects on metabolic homeostasis. The dominant source of FGF21 in the circulation is the liver.

Objective And Methods: To analyze the physiological functions of hepatic FGF21, we generated a hepatocyte-specific knockout model (LKO) by mating albumin-Cre mice with FGF21 flox/flox (fl/fl) mice and challenged it with different nutritional models.

Results: Mice fed a ketogenic diet typically show increased energy expenditure; this effect was attenuated in LKO mice. LKO on KD also developed hepatic pathology and altered hepatic lipid homeostasis. When evaluated using hyperinsulinemic-euglycemic clamps, glucose infusion rates, hepatic glucose production, and glucose uptake were similar between fl/fl and LKO DIO mice.

Conclusions: We conclude that liver-derived FGF21 is important for complete adaptation to ketosis but has a more limited role in the regulation of glycemic homeostasis.
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http://dx.doi.org/10.1007/s12020-019-02124-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948212PMC
January 2020

MCH Regulates SIRT1/FoxO1 and Reduces POMC Neuronal Activity to Induce Hyperphagia, Adiposity, and Glucose Intolerance.

Diabetes 2019 12 16;68(12):2210-2222. Epub 2019 Sep 16.

Department of Physiology, CIMUS, Universidad de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain

Melanin-concentrating hormone (MCH) is an important regulator of food intake, glucose metabolism, and adiposity. However, the mechanisms mediating these actions remain largely unknown. We used pharmacological and genetic approaches to show that the sirtuin 1 (SIRT1)/FoxO1 signaling pathway in the hypothalamic arcuate nucleus (ARC) mediates MCH-induced feeding, adiposity, and glucose intolerance. MCH reduces proopiomelanocortin (POMC) neuronal activity, and the SIRT1/FoxO1 pathway regulates the inhibitory effect of MCH on POMC expression. Remarkably, the metabolic actions of MCH are compromised in mice lacking SIRT1 specifically in POMC neurons. Of note, the actions of MCH are independent of agouti-related peptide (AgRP) neurons because inhibition of γ-aminobutyric acid receptor in the ARC did not prevent the orexigenic action of MCH, and the hypophagic effect of MCH silencing was maintained after chemogenetic stimulation of AgRP neurons. Central SIRT1 is required for MCH-induced weight gain through its actions on the sympathetic nervous system. The central MCH knockdown causes hypophagia and weight loss in diet-induced obese wild-type mice; however, these effects were abolished in mice overexpressing SIRT1 fed a high-fat diet. These data reveal the neuronal basis for the effects of MCH on food intake, body weight, and glucose metabolism and highlight the relevance of SIRT1/FoxO1 pathway in obesity.
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http://dx.doi.org/10.2337/db19-0029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868473PMC
December 2019

Mediation of the Acute Stress Response by the Skeleton.

Cell Metab 2019 11 12;30(5):890-902.e8. Epub 2019 Sep 12.

Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address:

We hypothesized that bone evolved, in part, to enhance the ability of bony vertebrates to escape danger in the wild. In support of this notion, we show here that a bone-derived signal is necessary to develop an acute stress response (ASR). Indeed, exposure to various types of stressors in mice, rats (rodents), and humans leads to a rapid and selective surge of circulating bioactive osteocalcin because stressors favor the uptake by osteoblasts of glutamate, which prevents inactivation of osteocalcin prior to its secretion. Osteocalcin permits manifestations of the ASR to unfold by signaling in post-synaptic parasympathetic neurons to inhibit their activity, thereby leaving the sympathetic tone unopposed. Like wild-type animals, adrenalectomized rodents and adrenal-insufficient patients can develop an ASR, and genetic studies suggest that this is due to their high circulating osteocalcin levels. We propose that osteocalcin defines a bony-vertebrate-specific endocrine mediation of the ASR.
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http://dx.doi.org/10.1016/j.cmet.2019.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834912PMC
November 2019

Central nicotine induces browning through hypothalamic κ opioid receptor.

Nat Commun 2019 09 6;10(1):4037. Epub 2019 Sep 6.

Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782, Santiago de Compostela, Spain.

Increased body weight is a major factor that interferes with smoking cessation. Nicotine, the main bioactive compound in tobacco, has been demonstrated to have an impact on energy balance, since it affects both feeding and energy expenditure at the central level. Among the central actions of nicotine on body weight, much attention has been focused on its effect on brown adipose tissue (BAT) thermogenesis, though its effect on browning of white adipose tissue (WAT) is unclear. Here, we show that nicotine induces the browning of WAT through a central mechanism and that this effect is dependent on the κ opioid receptor (KOR), specifically in the lateral hypothalamic area (LHA). Consistent with these findings, smokers show higher levels of uncoupling protein 1 (UCP1) expression in WAT, which correlates with smoking status. These data demonstrate that central nicotine-induced modulation of WAT browning may be a target against human obesity.
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http://dx.doi.org/10.1038/s41467-019-12004-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731305PMC
September 2019

Smooth Muscle Cell-Specific Disruption of the BBSome Causes Vascular Dysfunction.

Hypertension 2019 10 19;74(4):817-825. Epub 2019 Aug 19.

From the Department of Pharmacology (J.J.R., D.-F.G., D.A.M., K.R.), University of Iowa Carver College of Medicine.

The BBSome-a complex consisting of 8 Bardet-Biedl syndrome proteins-is involved in the regulation of various cellular processes. Recently, the BBSome complex has emerged as an important regulator of cardiovascular function with implications for disease. In this study, we examined the role of the BBSome in vascular smooth muscle and its effects on the regulation of cardiovascular function. Smooth muscle-specific disruption of the BBSome through tamoxifen-inducible deletion of gene-a critical component of the BBSome complex-reduces relaxation and enhances contractility of vascular rings and increases aortic stiffness independent of changes in arterial blood pressure. Mechanistically, we demonstrate that smooth muscle gene deletion increases vascular angiotensinogen gene expression implicating the renin-angiotensin system in these altered cardiovascular responses. Additionally, we report that smooth muscle-specific Bbs1 knockout mice demonstrate enhanced ET-1 (endothelin-1)-induced contractility of mesenteric arteries-an effect reversed by blockade of the AT1 (angiotensin type 1 receptor) with losartan. These findings highlight the importance of the smooth muscle BBSome in the control of vascular function and arterial stiffness through modulation of renin-angiotensin system signaling.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739154PMC
October 2019

Liver sympathetic denervation reverses obesity-induced hepatic steatosis.

J Physiol 2019 09 26;597(17):4565-4580. Epub 2019 Jul 26.

Department of Pharmacology and Physiology, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.

Key Points: Non-alcoholic fatty liver disease, characterized in part by elevated liver triglycerides (i.e. hepatic steatosis), is a growing health problem. In this study, we found that hepatic steatosis is associated with robust hepatic sympathetic overactivity. Removal of hepatic sympathetic nerves reduced obesity-induced hepatic steatosis. Liver sympathetic innervation modulated hepatic lipid acquisition pathways during obesity.

Abstract: Non-alcoholic fatty liver disease (NAFLD) affects 1 in 3 Americans and is a significant risk factor for type II diabetes mellitus, insulin resistance and hepatic carcinoma. Characterized in part by excessive hepatic triglyceride accumulation (i.e. hepatic steatosis), the incidence of NAFLD is increasing - in line with the growing obesity epidemic. The role of the autonomic nervous system in NAFLD remains unclear. Here, we show that chronic hepatic sympathetic overactivity mediates hepatic steatosis. Direct multiunit recordings of hepatic sympathetic nerve activity were obtained in high fat diet and normal chow fed male C57BL/6J mice. To reduce hepatic sympathetic nerve activity we utilized two approaches including pharmacological ablation of the sympathetic nerves and phenol-based hepatic sympathetic nerve denervation. Diet-induced NAFLD was associated with a nearly doubled firing rate of the hepatic sympathetic nerves, which was largely due to an increase in efferent nerve traffic. Furthermore, established high fat diet-induced hepatic steatosis was effectively reduced with pharmacological or phenol-based removal of the hepatic sympathetic nerves, independent of changes in body weight, caloric intake or adiposity. Ablation of liver sympathetic nerves was also associated with improvements in liver triglyceride accumulation pathways including free fatty acid uptake and de novo lipogenesis. These findings highlight an unrecognized pathogenic link between liver sympathetic outflow and hepatic steatosis and suggest that manipulation of the liver sympathetic nerves may represent a novel therapeutic strategy for NAFLD.
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http://dx.doi.org/10.1113/JP277994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716997PMC
September 2019

The Bardet-Biedl syndrome protein complex regulates cell migration and tissue repair through a Cullin-3/RhoA pathway.

Am J Physiol Cell Physiol 2019 09 19;317(3):C457-C465. Epub 2019 Jun 19.

Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa.

Cell motility and migration play critical roles in various physiological processes and disease states. Here, we show that the BBBsome, a macromolecule composed of eight Bardet-Biedl syndrome (BBS) proteins including BBS1, is a critical determinant of cell migration and wound healing. Fibroblast cells derived from mice or humans harboring a homozygous missense mutation (BBS1) that disrupt the BBSome exhibit defects in migration and wound healing. Furthermore, we demonstrate that BBS1 mice have significantly delayed wound closure. In line with this, we provide data suggesting that BBS1 fibroblasts have impaired platelet-derived growth factor-AA (PDGF) receptor-α signaling, a key regulator of directional cell migration acting as a chemoattractant during postnatal migration responses such as wound healing. In addition, we show that BBS1 fibroblasts have upregulated RhoA expression and activity. The relevance of RhoA upregulation is demonstrated by the ability of RhoA-kinase inhibitor Y27632 to partially rescue the migration defect of BBS1 fibroblasts cells. We also show that accumulation of RhoA protein in BBS1 fibroblasts cells is associated with reduction and inactivation of the ubiquitin ligase Cullin-3. Consistent with this, Cullin-3 inhibition with MLN4924 is sufficient to reduce migration of normal fibroblasts. These data implicate the BBSome in cell motility and tissue repair through a mechanism that involves PDGF receptor signaling and Cullin-3-mediated control of RhoA.
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http://dx.doi.org/10.1152/ajpcell.00498.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766617PMC
September 2019

The BBSome in POMC and AgRP Neurons Is Necessary for Body Weight Regulation and Sorting of Metabolic Receptors.

Diabetes 2019 08 24;68(8):1591-1603. Epub 2019 May 24.

Department of Pharmacology, University of Iowa, Iowa City, IA

The BBSome, a complex of eight Bardet-Biedl syndrome (BBS) proteins involved in cilia function, has emerged as an important regulator of energy balance, but the underlying cellular and molecular mechanisms are not fully understood. Here, we show that the control of energy homeostasis by the anorexigenic proopiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons require intact BBSome. Targeted disruption of the BBSome by gene deletion in POMC or AgRP neurons increases body weight and adiposity. We demonstrate that obesity in mice lacking the gene in POMC neurons is associated with hyperphagia. Mechanistically, we present evidence implicating the BBSome in the trafficking of G protein-coupled neuropeptide Y Y2 receptor (NPYR) and serotonin 5-hydroxytryptamine (HT) receptor (5-HTR) to cilia and plasma membrane, respectively. Consistent with this, loss of the BBSome reduced cell surface expression of the 5-HTR, interfered with serotonin-evoked increase in intracellular calcium and membrane potential, and blunted the anorectic and weight-reducing responses evoked by the 5-HTR agonist, lorcaserin. Finally, we show that disruption of the BBSome causes the 5-HTR to be stalled in the late endosome. Our results demonstrate the significance of the hypothalamic BBSome for the control of energy balance through regulation of trafficking of important metabolic receptors.
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http://dx.doi.org/10.2337/db18-1088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692817PMC
August 2019

Mechanistic Target of Rapamycin Complex 1 Signaling Modulates Vascular Endothelial Function Through Reactive Oxygen Species.

J Am Heart Assoc 2019 05;8(9):e010662

1 Department of Pharmacology University of Iowa Carver College of Medicine Iowa City IA.

Background The mechanistic target of rapamycin complex 1 ( mTORC 1) is an important intracellular energy sensor that regulates gene expression and protein synthesis through its downstream signaling components, the S6-kinase and the ribosomal S6 protein. Recently, signaling arising from mTORC 1 has been implicated in regulation of the cardiovascular system with implications for disease. Here, we examined the contribution of mTORC 1 signaling to the regulation of vascular function. Methods and Results Activation of mTORC 1 pathway in aortic rings with leucine or an adenoviral vector expressing a constitutively active S6-kinase reduces endothelial-dependent vasorelaxation in an mTORC 1-dependent manner without affecting smooth muscle relaxation responses. Moreover, activation of mTORC 1 signaling in endothelial cells increases reactive oxygen species ( ROS ) generation and ROS gene expression resulting in a pro-oxidant gene environment. Blockade of ROS signaling with Tempol restores endothelial function in vascular rings with increased mTORC 1 activity indicating a crucial interaction between mTORC 1 and ROS signaling. We then tested the role of nuclear factor-κB transcriptional complex in connecting mTORC 1 and ROS signaling in endothelial cells. Blockade of inhibitor of nuclear factor κ-B kinase subunit β activity with BMS -345541 prevented the increased ROS generation associated with increased mTORC 1 activity in endothelial cells but did not improve vascular endothelial function in aortic rings with increased mTORC 1 and ROS signaling. Conclusions These results implicate mTORC 1 as a critical molecular signaling hub in the vascular endothelium in mediating vascular endothelial function through modulation of ROS signaling.
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http://dx.doi.org/10.1161/JAHA.118.010662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512105PMC
May 2019

Activation of ADAM17 (A Disintegrin and Metalloprotease 17) on Glutamatergic Neurons Selectively Promotes Sympathoexcitation.

Hypertension 2019 06;73(6):1266-1274

From the Department of Pharmacology and Experimental Therapeutics (J.X., S.M., E.L.), Louisiana State University Health Sciences Center, New Orleans.

Chronic activation of the brain renin-angiotensin system contributes to the development of hypertension by altering autonomic balance. Beyond the essential role of Ang II (angiotensin II) type 1 receptors, ADAM17 (A disintegrin and metalloprotease 17) is also found to promote brain renin-angiotensin system overactivation. ADAM17 is robustly expressed in various cell types within the central nervous system. The aim of this study was to determine whether ADAM17 modulates presympathetic neuronal activity to promote autonomic dysregulation in salt-sensitive hypertension. To test our hypothesis, ADAM17 was selectively knocked down in glutamatergic neurons using Cre-loxP technology. In mice lacking ADAM17 in glutamatergic neurons, the blood pressure increase induced by deoxycorticosterone acetate-salt treatment was blunted. Deoxycorticosterone acetate-salt significantly elevated cardiac and vascular sympathetic drive in control mice, while such effects were reduced in mice with ADAM17 knockdown. This blunted sympathoexcitation was extended to the spleen, with a lesser activation of the peripheral immune system, translating into a sequestration of circulating T cells within this organ, compared with controls. Within the paraventricular nucleus, Ang II-induced activation of kidney-related presympathetic glutamatergic neurons was reduced in ADAM17 knockdown mice, with the majority of cells no longer responding to Ang II stimulation, confirming the supportive role of ADAM17 in increasing presympathetic neuronal activity. Overall, our data highlight the pivotal role of neuronal ADAM17 in regulating sympathetic activity and demonstrate that activation of ADAM17 in glutamatergic neurons leads to a selective increase of sympathetic output, but not vagal tone, to specific organs, ultimately contributing to dysautonomia and salt-sensitive hypertension.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.12832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506373PMC
June 2019

Celastrol Reduces Obesity in MC4R Deficiency and Stimulates Sympathetic Nerve Activity Affecting Metabolic and Cardiovascular Functions.

Diabetes 2019 06 20;68(6):1210-1220. Epub 2019 Mar 20.

Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA

Leptin resistance is a hallmark of obesity with unclear etiology. Celastrol, a compound found in the roots of the and known to reduce endoplasmic reticulum (ER) stress, has recently emerged as a promising candidate to treat obesity by improving leptin sensitivity. However, the underlying neural mechanisms by which celastrol reduces obesity remain unclear. Using three different mouse models of obesity-diet-induced obesity (DIO), leptin receptor (LepR)-null, and melanocortin 4 receptor (MC4R)-null mice-in this study, we show that systemic celastrol administration substantially reduces food intake and body weight in MC4R-null comparable to DIO, proving the MC4R-independent antiobesity effect of celastrol. Body weight reduction was due to decreases in both fat and lean mass, and modest but significant body weight reduction was also observed in nonobese wild-type and LepR-null mice. Unexpectedly, celastrol upregulated proinflammatory cytokines without affecting genes involved in ER stress. Importantly, celastrol steadily increased sympathetic nerve activity to the brown fat and kidney with concordant increases of resting metabolic rate and arterial pressure. Our results suggest a previously unappreciated mechanism of action of celastrol in the regulation of energy homeostasis and highlight the need for careful consideration of its development as a safe antiobesity medication.
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http://dx.doi.org/10.2337/db18-1167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610022PMC
June 2019

Liver Derived FGF21 Maintains Core Body Temperature During Acute Cold Exposure.

Sci Rep 2019 01 24;9(1):630. Epub 2019 Jan 24.

Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.

Fibroblast Growth Factor 21 (FGF21) elicits an array of metabolic effects. However, the physiological role of FGF21 during thermal challenges is not clear. In this study, we assessed the tissue source of FGF21 and its site of action to regulate core body temperature in response to cold. Using mice lacking FGF21 specifically in the liver (FGF21 LivKO) or adipose tissues (FGF21 AdipoKO), we performed a series of cold exposure studies to examine the tissue specific induction of FGF21 in response to cold. We also examined the physiological site of FGF21 action during cold exposure by impairing FGF21 signaling to adipose tissues or the central nervous system (CNS) using genetic ablation of the FGF21 co-receptor β-klotho in adipose tissues (KLB AdipoKO) or pharmacological blockage of FGF21 signaling. We found that only liver-derived FGF21 enters circulation during acute cold exposure and is critical for thermoregulation. While FGF21 signaling directly to adipose tissues during cold is dispensable for thermoregulation, central FGF21 signaling is necessary for maximal sympathetic drive to brown adipose tissue to maintain thermoregulation during cold. These data demonstrate a previously unrecognized role for FGF21 in the maintenance of body temperature in response to cold.
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http://dx.doi.org/10.1038/s41598-018-37198-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345819PMC
January 2019

Adipocyte-secreted BMP8b mediates adrenergic-induced remodeling of the neuro-vascular network in adipose tissue.

Nat Commun 2018 11 26;9(1):4974. Epub 2018 Nov 26.

Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK.

Activation of brown adipose tissue-mediated thermogenesis is a strategy for tackling obesity and promoting metabolic health. BMP8b is secreted by brown/beige adipocytes and enhances energy dissipation. Here we show that adipocyte-secreted BMP8b contributes to adrenergic-induced remodeling of the neuro-vascular network in adipose tissue (AT). Overexpression of bmp8b in AT enhances browning of the subcutaneous depot and maximal thermogenic capacity. Moreover, BMP8b-induced browning, increased sympathetic innervation and vascularization of AT were maintained at 28 °C, a condition of low adrenergic output. This reinforces the local trophic effect of BMP8b. Innervation and vascular remodeling effects required BMP8b signaling through the adipocytes to 1) secrete neuregulin-4 (NRG4), which promotes sympathetic axon growth and branching in vitro, and 2) induce a pro-angiogenic transcriptional and secretory profile that promotes vascular sprouting. Thus, BMP8b and NRG4 can be considered as interconnected regulators of neuro-vascular remodeling in AT and are potential therapeutic targets in obesity.
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http://dx.doi.org/10.1038/s41467-018-07453-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255810PMC
November 2018