Publications by authors named "Darleen A Sandoval"

83 Publications

The Role of Elevated Branched-Chain Amino Acids in the Effects of Vertical Sleeve Gastrectomy to Reduce Weight and Improve Glucose Regulation.

Cell Rep 2020 10;33(2):108239

Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

Elevated levels of branched-chain amino acids (BCAAs) and their metabolites are strongly positively associated with obesity, insulin resistance, and type 2 diabetes. Bariatric surgery is among the best treatments for weight loss and associated morbidities. Clinical studies have reported that bariatric surgery decreases the circulating levels of BCAAs. The objective of this study was to test the hypothesis that reduced BCAA levels contribute to the metabolic improvements of sustained weight loss and improved glucose tolerance after vertical sleeve gastrectomy (VSG). We find that, as in humans, circulating BCAAs are significantly lower in VSG rats and mice. To increase circulating BCAAs, we tested mice with either increased dietary intake of BCAAs or impaired BCAA catabolism by total body deletion of mitochondrial phosphatase 2C (Pp2cm). Our results show that a decrease in circulating BCAAs is not necessary for sustained body weight loss and improved glucose tolerance after VSG.
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http://dx.doi.org/10.1016/j.celrep.2020.108239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605275PMC
October 2020

Assessment of the role of FGF15 in mediating the metabolic outcomes of murine Vertical Sleeve Gastrectomy (VSG).

Am J Physiol Gastrointest Liver Physiol 2020 Sep 23. Epub 2020 Sep 23.

Pediatrics, Children's Hospital of Los Angeles, United States.

Vertical sleeve gastrectomy (VSG) is the best current therapy for remission of obesity and its co-morbidities. It is understood to alter the enterohepatic circulation of bile acids in vivo. Fibroblast growth factor 19 (FGF19) in human and its murine orthologue Fgf15 plays a pivotal role in this bile acid driven enterohepatic signaling. The present study evaluated the metabolic outcomes of VSG in Fgf15 deficient mice. 6-8 weeks old male wildtype mice (WT) and Fgf15 deficient mice (KO) were fed a high fat diet (HFD) for 8 weeks. At 8 week of diet, both WT and KO mice were randomly distributed to VSG or sham surgery. Post-surgery, mice were observed for 8 weeks while fed a HFD and then euthanized to collect tissues for experimental analysis. Fgf15 deficient (KO) mice lost weight post VSG, but glucose tolerance in KO mice did not improve post VSG compared to WT mice. Enteroids derived from WT and KO mice proliferated with bile acid exposure in vitro. Post VSG both WT and KO mice had similarly altered bile acid enterohepatic flux, however Fgf15 deficient mice post VSG had increased hepatic accumulation of free and esterified cholesterol leading to lipotoxicity related ER stress, inflammasome activation, and increased Fgf21 expression. Intact Fgf15 mediated enterohepatic bile acid signaling, but not changes in bile acid flux, appear to be important for the metabolic improvements post-murine bariatric surgery. These novel data introduce a potential point of distinction between bile acids acting as ligands compared to their canonical downstream signaling pathways.
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http://dx.doi.org/10.1152/ajpgi.00175.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792670PMC
September 2020

Intestine-selective reduction of Gcg expression reveals the importance of the distal gut for GLP-1 secretion.

Mol Metab 2020 07 9;37:100990. Epub 2020 Apr 9.

Department of Medicine and the Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

Objective: Glucagon-like peptide-1 is a nutrient-sensitive hormone secreted from enteroendocrine L cells within the small and large bowel. Although GLP-1 levels rise rapidly in response to food ingestion, the greatest density of L cells is localized to the distal small bowel and colon. Here, we assessed the importance of the distal gut in the acute L cell response to diverse secretagogues.

Methods: Circulating levels of glucose and plasma GLP-1 were measured in response to the administration of L cell secretagogues in wild-type mice and in mice with (1) genetic reduction of Gcg expression throughout the small bowel and large bowel (Gcg) and (2) selective reduction of Gcg expression in the distal gut (Gcg).

Results: The acute GLP-1 response to olive oil or arginine administration was markedly diminished in Gcg but preserved in Gcg mice. In contrast, the increase in plasma GLP-1 levels following the administration of the GPR119 agonist AR231453, or the melanocortin-4 receptor (MC4R) agonist LY2112688, was markedly diminished in the Gcg mice. The GLP-1 response to LPS was also markedly attenuated in the Gcg mice and remained submaximal in the Gcg mice. Doses of metformin sufficient to lower glucose and increase GLP-1 levels in the Gcg mice retained their glucoregulatory activity, yet they failed to increase GLP-1 levels in the Gcg mice. Surprisingly, the actions of metformin to increase plasma GLP-1 levels were substantially attenuated in the Gcg mice.

Conclusion: These findings further establish the importance of the proximal gut for the acute response to nutrient-related GLP-1 secretagogues. In contrast, we identify essential contributions of the distal gut to (i) the rapid induction of circulating GLP-1 levels in response to pharmacological selective agonism of G-protein-coupled receptors, (ii) the increased GLP-1 levels following the activation of Toll-Like Receptors with LPS, and iii) the acute GLP-1 response to metformin. Collectively, these results reveal that distal gut Gcg + endocrine cells are rapid responders to structurally and functionally diverse GLP-1 secretagogues.
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http://dx.doi.org/10.1016/j.molmet.2020.100990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200938PMC
July 2020

Glucagon-Like Peptide-1: Actions and Influence on Pancreatic Hormone Function.

Compr Physiol 2020 03 12;10(2):577-595. Epub 2020 Mar 12.

Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.

GLP-1 was described as an incretin over 30 years ago. GLP-1 is encoded by the preproglucagon gene (Gcg), which is expressed in the intestine, the pancreas, and the central nervous system. GLP-1 activates GLP-1 receptors (GLP-1r) on the β-cell to induce insulin secretion in a glucose-dependent manner. GLP-1 also inhibits α-cell secretion of glucagon. As few, if any, GLP-1r are expressed on α-cells, indirect regulation, via β- or δ-cell products has been thought to be the primary mechanism by which GLP-1 inhibits glucagon secretion. However, recent work suggests that there is sufficient expression of GLP-1r on α-cells for direct regulation as well. Although the predominant source of circulating GLP-1 is the intestine, the α-cell becomes a source of GLP-1 when the islet is metabolically stressed. Recent work suggests the possibility that this source of GLP-1 is also be important in regulating nutrient-induced insulin secretion in a paracrine fashion. More work is also accumulating regarding the role of glucagon, another Gcg-derived protein produced by the α-cell, in stimulating insulin secretion by acting on GLP-1r. Altogether, these data clearly demonstrate the important role of Gcg-derived peptides in regulating insulin secretion. Because of GLP-1's important role in glucose homeostasis, it has been implicated in the success of bariatric surgery and has been successfully targeted for the treatment of type 2 diabetes mellitus. © 2020 American Physiological Society. Compr Physiol 10:577-595, 2020.
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http://dx.doi.org/10.1002/cphy.c190025DOI Listing
March 2020

Ventromedial hypothalamic nucleus neuronal subset regulates blood glucose independently of insulin.

J Clin Invest 2020 06;130(6):2943-2952

Department of Internal Medicine and.

To identify neurons that specifically increase blood glucose from among the diversely functioning cell types in the ventromedial hypothalamic nucleus (VMN), we studied the cholecystokinin receptor B-expressing (CCKBR-expressing) VMN targets of glucose-elevating parabrachial nucleus neurons. Activation of these VMNCCKBR neurons increased blood glucose. Furthermore, although silencing the broader VMN decreased energy expenditure and promoted weight gain without altering blood glucose levels, silencing VMNCCKBR neurons decreased hIepatic glucose production, insulin-independently decreasing blood glucose without altering energy balance. Silencing VMNCCKBR neurons also impaired the counterregulatory response to insulin-induced hypoglycemia and glucoprivation and replicated hypoglycemia-associated autonomic failure. Hence, VMNCCKBR cells represent a specialized subset of VMN cells that function to elevate glucose. These cells not only mediate the allostatic response to hypoglycemia but also modulate the homeostatic setpoint for blood glucose in an insulin-independent manner, consistent with a role for the brain in the insulin-independent control of glucose homeostasis.
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http://dx.doi.org/10.1172/JCI134135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260001PMC
June 2020

Continuous glucose monitoring reveals glycemic variability and hypoglycemia after vertical sleeve gastrectomy in rats.

Mol Metab 2020 02 24;32:148-159. Epub 2019 Dec 24.

Department of Surgery, University of Michigan, Ann Arbor, MI 48105, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48105, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48105, USA. Electronic address:

Objective: Post-bariatric surgery hypoglycemia (PBH) is defined as the presence of neuroglycopenic symptoms accompanied by postprandial hypoglycemia in bariatric surgery patients. Recent clinical studies using continuous glucose monitoring (CGM) technology revealed that PBH is more frequently observed in vertical sleeve gastrectomy (VSG) patients than previously recognized. PBH cannot be alleviated by current medication. Therefore, a model system to investigate the mechanism and treatment is required.

Methods: We used CGM in a rat model of VSG and monitored the occurrence of glycemic variability and hypoglycemia in various meal conditions for 4 weeks after surgery. Another cohort of VSG rats with CGM was used to investigate whether the blockade of glucagon-like peptide-1 receptor (GLP-1R) signaling alleviates these symptoms. A mouse VSG model was used to investigate whether the impaired glucose counterregulatory system causes postprandial hypoglycemia.

Results: Like in humans, rats have increased glycemic variability and hypoglycemia after VSG. Postprandial hypoglycemia was specifically detected after liquid versus solid meals. Further, the blockade of GLP-1R signaling raises the glucose nadir but does not affect glycemic variability.

Conclusions: Rat bariatric surgery duplicates many features of human post-bariatric surgery hypoglycemia including postprandial hypoglycemia and glycemic variability, while blockade of GLP-1R signaling prevents hypoglycemia but not the variability.
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http://dx.doi.org/10.1016/j.molmet.2019.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005148PMC
February 2020

Calcitonin Receptor Neurons in the Mouse Nucleus Tractus Solitarius Control Energy Balance via the Non-aversive Suppression of Feeding.

Cell Metab 2020 02 16;31(2):301-312.e5. Epub 2020 Jan 16.

Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48105, USA; Division of Endocrinology, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48105, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48105, USA; Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48105, USA. Electronic address:

To understand hindbrain pathways involved in the control of food intake, we examined roles for calcitonin receptor (CALCR)-containing neurons in the NTS. Ablation of NTS Calcr abrogated the long-term suppression of food intake, but not aversive responses, by CALCR agonists. Similarly, activating Calcr neurons decreased food intake and body weight but (unlike neighboring Cck cells) failed to promote aversion, revealing that Calcr neurons mediate a non-aversive suppression of food intake. While both Calcr and Cck neurons decreased feeding via projections to the PBN, Cck cells activated aversive CGRP cells while Calcr cells activated distinct non-CGRP PBN cells. Hence, Calcr cells suppress feeding via non-aversive, non-CGRP PBN targets. Additionally, silencing Calcr cells blunted food intake suppression by gut peptides and nutrients, increasing food intake and promoting obesity. Hence, Calcr neurons define a hindbrain system that participates in physiological energy balance and suppresses food intake without activating aversive systems.
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http://dx.doi.org/10.1016/j.cmet.2019.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104375PMC
February 2020

A rodent model of partial intestinal diversion: a novel metabolic operation.

Surg Obes Relat Dis 2020 Feb 7;16(2):270-281. Epub 2019 Nov 7.

Department of Surgery, University of Michigan, Ann Arbor, Michigan.

Background: Metabolic surgery is safe and the most effective therapy for obesity and its co-morbidities. New procedures may allow for better tailoring of metabolic surgery to the individual patient.

Objective: To evaluate the impact, comparative effectiveness, and mechanisms of the partial intestinal diversion (PID), vertical sleeve gastrectomy (VSG), and the combination of PID and VSG on weight and glucose regulation.

Setting: University research facility, United States.

Methods: Three cohorts of high-fat diet-induced obese male rats were randomized to distal PID (DPID), proximal PID (PPID), VSG, VSG and DPID (VSG/DPID), or sham operation (Sham). Animals were followed for 11 (cohort 1) or 10 (cohorts 2 and 3) weeks. Outcomes included weight and composition, food intake, glucose metabolism, lipids, bile acids, and energy balance. Statistical comparisons were performed using Tukey's multiple comparison test applied to analysis of variance.

Results: DPID and not PPID resulted in significant weight and body fat reductions relative to Sham. Improved glucose tolerance was seen in all surgical groups though this reached statistical significance for only DPID and VSG compared with Sham. Improvements in baseline glucose and insulin, corresponding insulin resistance, and plasma lipids were noted in DPID compared with Sham. Though the magnitude of weight and body composition changes and metabolic benefit tended to be larger for VSG relative to DPID, it only reached statistical significance for lipids. VSG and VSG/DPID resulted in similar outcomes. Markedly reduced food intake occurred after VSG and more modestly after DPID. Stool caloric content was higher in DPID relative to all groups.

Conclusions: DPID is an effective metabolic operation resulting in notable weight and fat loss and metabolic improvement relative to sham-operated rodents. Interestingly, combining VSG with DPID added little additional benefit to the effects of VSG.
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http://dx.doi.org/10.1016/j.soard.2019.10.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024579PMC
February 2020

Bromocriptine improves glucose tolerance independent of circadian timing, prolactin, or the melanocortin-4 receptor.

Am J Physiol Endocrinol Metab 2020 01 3;318(1):E62-E71. Epub 2019 Dec 3.

Department of Biological Sciences, Marquette University, Milwaukee, Wisconsin.

Bromocriptine, a dopamine D2 receptor agonist originally used for the treatment of hyperprolactinemia, is largely successful in reducing hyperglycemia and improving glucose tolerance in type 2 diabetics. However, the mechanism behind bromocriptine's effect on glucose intolerance is unclear. Here, we tested three hypotheses, that bromocriptine may exert its effects on glucose metabolism by ) decreasing prolactin secretion, ) indirectly increasing activity of key melanocortin receptors in the central nervous system, or ) improving/restoring circadian rhythms. Using a diet-induced obese (DIO) mouse model, we established that a 2-wk treatment of bromocriptine is robustly effective at improving glucose tolerance. We then demonstrated that bromocriptine is effective at improving the glucose tolerance of both DIO prolactin-deficient and melanocortin-4 receptor (MC4R)-deficient mice, pointing to bromocriptine's ability to affect glucose tolerance independently of prolactin or MC4R signaling. Finally, we tested bromocriptine's dependence on the circadian system by testing its effectiveness in environmental (e.g., repeated shifts to the light-dark cycle) and genetic (e.g., the mutant mouse) models of circadian disruption. In both models of circadian disruption, bromocriptine was effective at improving glucose tolerance, indicating that a functional or well-aligned endogenous clock is not necessary for bromocriptine's effects on glucose metabolism. Taken together, these results do not support the role of prolactin, MC4R, or the circadian clock as integral to bromocriptine's underlying mechanism. Instead, we find that bromocriptine is a robust diabetic treatment and resilient to genetically induced obesity, diabetes, and circadian disruption.
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http://dx.doi.org/10.1152/ajpendo.00325.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985791PMC
January 2020

Glycemic effect of pancreatic preproglucagon in mouse sleeve gastrectomy.

JCI Insight 2019 10 17;4(20). Epub 2019 Oct 17.

Intestinally derived glucagon-like peptide-1 (GLP-1), encoded by the preproglucagon (Gcg) gene, is believed to function as an incretin. However, our previous work questioned this dogma and demonstrated that pancreatic peptides rather than intestinal Gcg peptides, including GLP-1, are a primary regulator of glucose homeostasis in normal mice. The objective of these experiments was to determine whether changes in nutrition or alteration of gut hormone secretion by bariatric surgery would result in a larger role for intestinal GLP-1 in the regulation of insulin secretion and glucose homeostasis. Multiple transgenic models, including mouse models with intestine- or pancreas tissue-specific Gcg expression and a whole-body Gcg-null mouse model, were generated to study the role of organ-specific GLP-1 production on glucose homeostasis under dietary-induced obesity and after weight loss from bariatric surgery (vertical sleeve gastrectomy; VSG). Our findings indicated that the intestine is a major source of circulating GLP-1 after various nutrient and surgical stimuli. However, even with the 4-fold increase in intestinally derived GLP-1 with VSG, it is pancreatic peptides, not intestinal Gcg peptides, that are necessary for surgery-induced improvements in glucose homeostasis.
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http://dx.doi.org/10.1172/jci.insight.129452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824314PMC
October 2019

Gut-Proglucagon-Derived Peptides Are Essential for Regulating Glucose Homeostasis in Mice.

Cell Metab 2019 11 5;30(5):976-986.e3. Epub 2019 Sep 5.

Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, ON M5G1X5, Canada. Electronic address:

The importance of pancreatic versus intestinal-derived GLP-1 for glucose homeostasis is controversial. We detected active GLP-1 in the mouse and human pancreas, albeit at extremely low levels relative to glucagon. Accordingly, to elucidate the metabolic importance of intestinal proglucagon-derived peptides (PGDPs), we generated mice with reduction of Gcg expression within the distal (Gcg) or entire (Gcg) gut. Substantial reduction of gut Gcg expression markedly reduced circulating levels of GLP-1, and impaired glucose homeostasis, associated with increased levels of GIP, and accelerated gastric emptying. Gcg mice similarly exhibited lower circulating GLP-1 and impaired oral glucose tolerance. Nevertheless, plasma levels of insulin remained normal following glucose administration in the absence of gut-derived GLP-1. Collectively, our findings identify the essential importance of gut-derived PGDPs for maintaining levels of circulating GLP-1, control of gastric emptying, and glucose homeostasis.
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http://dx.doi.org/10.1016/j.cmet.2019.08.009DOI Listing
November 2019

The role of GIP and pancreatic GLP-1 in the glucoregulatory effect of DPP-4 inhibition in mice.

Diabetologia 2019 10 14;62(10):1928-1937. Epub 2019 Aug 14.

Department of Surgery, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI, 48109, USA.

Aims/hypothesis: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two peptides that function to promote insulin secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase the bioavailability of both GLP-1 and GIP but the dogma continues to be that it is the increase in GLP-1 that contributes to the improved glucose homeostasis. We have previously demonstrated that pancreatic rather than intestinal GLP-1 is necessary for improvements in glucose homeostasis in mice. Therefore, we hypothesise that a combination of pancreatic GLP-1 and GIP is necessary for the full effect of DPP-4 inhibitors on glucose homeostasis.

Methods: We have genetically engineered mouse lines in which the preproglucagon gene (Gcg) is absent in the entire body (GcgRA) or is expressed exclusively in the intestine (GcgRA) or pancreas and duodenum (GcgRA). These mice were used to examine oral glucose tolerance and GLP-1 and GIP responses to a DPP-4 inhibitor alone, or in combination with incretin receptor antagonists.

Results: Administration of the DPP-4 inhibitor, linagliptin, improved glucose tolerance in GcgRA mice and control littermates and in GcgRA and GcgRA mice. The potent GLP-1 receptor antagonist, exendin-[9-39] (Ex9), blunted improvements in glucose tolerance in linagliptin-treated control mice and in GcgRA mice. Ex9 had no effect on glucose tolerance in linagliptin-treated GcgRA or in GcgRA mice. In addition to GLP-1, linagliptin also increased postprandial plasma levels of GIP to a similar degree in all genotypes. When linagliptin was co-administered with a GIP-antagonising antibody, the impact of linagliptin was partially blunted in wild-type mice and was fully blocked in GcgRA mice.

Conclusions/interpretation: Taken together, these data suggest that increases in pancreatic GLP-1 and GIP are necessary for the full effect of DPP-4 inhibitors on glucose tolerance.
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http://dx.doi.org/10.1007/s00125-019-4963-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732043PMC
October 2019

G-CSF partially mediates effects of sleeve gastrectomy on the bone marrow niche.

J Clin Invest 2019 05 6;129(6):2404-2416. Epub 2019 May 6.

Department of Molecular & Integrative Physiology.

Bariatric surgeries are integral to the management of obesity and its metabolic complications. However, these surgeries cause bone loss and increase fracture risk through poorly understood mechanisms. In a mouse model, vertical sleeve gastrectomy (VSG) caused trabecular and cortical bone loss that was independent of sex, body weight, and diet, and this loss was characterized by impaired osteoid mineralization and bone formation. VSG had a profound effect on the bone marrow niche, with rapid loss of marrow adipose tissue, and expansion of myeloid cellularity, leading to increased circulating neutrophils. Following VSG, circulating granulocyte-colony stimulating factor (G-CSF) was increased in mice, and was transiently elevated in a longitudinal study of humans. Elevation of G-CSF was found to recapitulate many effects of VSG on bone and the marrow niche. In addition to stimulatory effects of G-CSF on myelopoiesis, endogenous G-CSF suppressed development of marrow adipocytes and hindered accrual of peak cortical and trabecular bone. Effects of VSG on induction of neutrophils and depletion of marrow adiposity were reduced in mice deficient for G-CSF; however, bone mass was not influenced. Although not a primary mechanism for bone loss with VSG, G-CSF plays an intermediary role for effects of VSG on the bone marrow niche.
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http://dx.doi.org/10.1172/JCI126173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546463PMC
May 2019

Inflammatory responses to dietary and surgical weight loss in male and female mice.

Biol Sex Differ 2019 04 3;10(1):16. Epub 2019 Apr 3.

Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA.

Background: Weight loss by surgery or lifestyle changes is strongly recommended for obese individuals to improve metabolic health, but the underlying impairments that persist from a history of obesity remain unclear. Recent investigations demonstrate a persistent inflammatory state with weight loss and bariatric surgery, but the mechanism and impact are not fully understood. Additionally, these studies have not been performed in females although women are the majority of individuals undergoing weight loss interventions.

Methods: The goal of this study was to determine the sex differences in metabolically induced inflammation after dietary weight loss (WL) or bariatric surgery. Following a 60% high-fat diet (HFD) for 12 weeks, C57Bl/6j mice underwent either a dietary switch to normal chow for WL or vertical sleeve gastrectomy (VSG) and were evaluated 8 weeks after intervention. WL effects on myelopoiesis were further evaluated with bone marrow chimeras.

Results: Both sexes had a decrease in adiposity and total weight following WL or VSG intervention. With HFD, females had very little inflammation and no further increase with WL, but males had persistent inflammation even after WL despite metabolic improvement. Interestingly, after VSG, myeloid inflammation was increased in the livers of males and to a lesser extent in females.

Conclusions: These studies demonstrate that regardless of sex, it is critical to assess an individuals' history of obesity rather than just rely on current weight status in medical decision-making. There are long-lasting effects on tissue inflammation in both sexes especially with surgical weight loss. Dietary change is overall most effective to improve meta-inflammation in obese males on its own or in combination with surgical weight loss.
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http://dx.doi.org/10.1186/s13293-019-0229-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446331PMC
April 2019

Mechanisms for the metabolic success of bariatric surgery.

J Neuroendocrinol 2019 05 10;31(5):e12708. Epub 2019 Apr 10.

Department of Surgery, University of Michigan, Ann Arbor, Michigan.

To date, bariatric surgery remains the most effective strategy for the treatment of obesity and its comorbidities. However, given the enormity of the obesity epidemic, and sometimes variable results, it is not a feasible strategy for the treatment of all obese patients. A simple PubMed search for 'bariatric surgery' reveals over 28 000 papers that have been published since the 1940s when the first bariatric surgeries were performed. However, there is still an incomplete understanding of the mechanisms for the weight loss and metabolic success of surgery. An understanding of the mechanisms is important because it may lead to greater understanding of the pathophysiology of obesity and thus surgery-alternative strategies for the treatment of all obese patients. In this review, the potential mechanisms that underlie the success of surgery are discussed, with a focus on the potential endocrine, neural and other circulatory factors (eg, bile acids) that have been proposed to play a role.
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http://dx.doi.org/10.1111/jne.12708DOI Listing
May 2019

Oea Signaling Pathways and the Metabolic Benefits of Vertical Sleeve Gastrectomy.

Ann Surg 2020 03;271(3):509-518

University of Michigan, Ann Arbor, MI.

Objective: The aim of this study was to determine whether downstream [peroxisome proliferator-activated-receptor alpha (PPARα) and the G-protein coupled receptor, GPR119] and upstream (a fatty acid translocase, CD36) signaling targets of N-oleoylethanolamide (OEA) were necessary for weight loss, metabolic improvements, and diet preference following vertical sleeve gastrectomy (VSG).

Summary Background Data: OEA is an anorectic N-acylethanolamine produced from dietary fats within the intestinal lumen that can modulate lipid metabolism, insulin secretion, and energy expenditure by activating targets such as PPARα and GPR119.

Methods: Diet-induced obese mice, including wild-type or whole body knockout (KO) of PPARα, GPR119, and CD36, were stratified to either VSG or sham surgery before body weight, body composition, diet preference, and glucose and lipid metabolic endpoints were assessed.

Results: We found increased duodenal production of OEA and expression of both GPR119 and CD36 were upregulated in wild-type mice after VSG. However, weight loss and glucose tolerance were improved in response to VSG in PPARαKO, GPR119KO, and CD36KO mice. In fact, VSG corrected hepatic triglyceride dysregulation in CD36KO mice, and circulating triglyceride and cholesterol levels in PPARαKO mice. Lastly, we found PPARα-mediated signaling contributes to macronutrient preference independent of VSG, while removal of CD36 signaling blunts the VSG-induced shift toward carbohydrate preference.

Conclusions: In the search for more effective and less invasive therapies to help reverse the global acceleration of obesity and obesity-related disease OEA is a promising candidate; however, our data indicate that it is not an underlying mechanism of the effectiveness of VSG.
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http://dx.doi.org/10.1097/SLA.0000000000003093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451489PMC
March 2020

Vertical sleeve gastrectomy improves ventilatory drive through a leptin-dependent mechanism.

JCI Insight 2019 Jan 10;4(1). Epub 2019 Jan 10.

Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.

Obesity hypoventilation syndrome (OHS) is a serious disorder characterized by daytime hypercapnia, disordered breathing, and a reduction in chemosensitivity. Vertical sleeve gastrectomy (VSG), a bariatric surgical procedure resulting in weight loss and weight-independent improvements in glucose metabolism, has been observed to substantially improve sleep-disordered breathing. However, it is unclear if the ventilatory effects of VSG are secondary to weight loss or the marked change in metabolic physiology. Using preclinical mouse models, we found that VSG leads to an improvement in the hypercapnic ventilatory response (HCVR) and reductions in circulating leptin levels independent of reductions in body mass, fat mass, and caloric intake. In the absence of leptin, VSG continues to improve body mass, fat mass, and glucose tolerance in ob/ob mice but no longer affects HCVR. However, the HCVR of ob/ob mice can be returned to wild-type levels with leptin treatment. These data demonstrate that VSG improves chemosensitivity and ventilatory drive via a leptin-dependent mechanism. Clinically, these data downgrade the relative contribution of physical, mechanical load in the pathogenesis of OHS, and instead point to physiological components of obesity, including alterations in leptin signaling, as key drivers in OHS.
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http://dx.doi.org/10.1172/jci.insight.124469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485355PMC
January 2019

Liraglutide Modulates Appetite and Body Weight Through Glucagon-Like Peptide 1 Receptor-Expressing Glutamatergic Neurons.

Diabetes 2018 08 18;67(8):1538-1548. Epub 2018 May 18.

Department of Pediatrics, University of Michigan, Ann Arbor, MI

Glucagon-like peptide 1 receptor (GLP-1R) agonists are U.S. Food and Drug Administration-approved weight loss drugs. Despite their widespread use, the sites of action through which GLP-1R agonists (GLP1RAs) affect appetite and body weight are still not fully understood. We determined whether GLP-1Rs in either GABAergic or glutamatergic neurons are necessary for the short- and long-term effects of the GLP1RA liraglutide on food intake, visceral illness, body weight, and neural network activation. We found that mice lacking GLP-1Rs in -expressing GABAergic neurons responded identically to controls in all parameters measured, whereas deletion of GLP-1Rs in -expressing glutamatergic neurons eliminated liraglutide-induced weight loss and visceral illness and severely attenuated its effects on feeding. Concomitantly, deletion of GLP-1Rs from glutamatergic neurons completely abolished the neural network activation observed after liraglutide administration. We conclude that liraglutide activates a dispersed but discrete neural network to mediate its physiological effects and that these effects require GLP-1R expression on glutamatergic but not GABAergic neurons.
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http://dx.doi.org/10.2337/db17-1385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054439PMC
August 2018

Vertical sleeve gastrectomy corrects metabolic perturbations in a low-exercise capacity rat model.

Mol Metab 2018 05 26;11:189-196. Epub 2018 Feb 26.

Department of Surgery, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Objective: Bariatric surgery is currently our most effective strategy at weight loss, yet the mechanisms for its success remain unknown. Low exercise capacity, in humans and rodents, predicts poor metabolic outcome. The objective of this manuscript was to determine if bariatric surgery could restore metabolic perturbations in rats with low intrinsic exercise capacity.

Methods: We performed vertical sleeve gastrectomy (VSG) or sham surgery in high fat-fed rats selectively bred for low running capacity.

Results: We found that VSG reduced body mass through a reduction in fat mass, caused early reductions in food intake, and shifted macronutrient preference away from fat and toward carbohydrates. VSG had no impact on basal glucose but did improve the return to baseline after an oral glucose load. As has been shown previously, VSG increased postprandial insulin, GLP-1, and bile acids. There was no significant impact of VSG on plasma triglycerides, hepatic triglycerides, or cholesterol. Interestingly, the brown adipose tissue to white adipose tissue ratio tended to be greater in VSG compared to sham surgery animals. While VSG positively impacted several aspects of metabolism, it did not enhance maximal oxygen capacity and seemed to lower metabolic efficiency as indicated by lower resting oxygen consumption and fat and carbohydrate oxidation.

Conclusion: VSG can improve the metabolic status of animals with a low exercise capacity independently of exercise capacity.
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http://dx.doi.org/10.1016/j.molmet.2018.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001357PMC
May 2018

Signalling from the periphery to the brain that regulates energy homeostasis.

Nat Rev Neurosci 2018 04 22;19(4):185-196. Epub 2018 Feb 22.

Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA.

The CNS regulates body weight; however, we still lack a clear understanding of what drives decisions about when, how much and what to eat. A vast array of peripheral signals provides information to the CNS regarding fluctuations in energy status. The CNS then integrates this information to influence acute feeding behaviour and long-term energy homeostasis. Previous paradigms have delegated the control of long-term energy homeostasis to the hypothalamus and short-term changes in feeding behaviour to the hindbrain. However, recent studies have identified target hindbrain neurocircuitry that integrates the orchestration of individual bouts of ingestion with the long-term regulation of energy balance.
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http://dx.doi.org/10.1038/nrn.2018.8DOI Listing
April 2018

The glucagon-like peptide-1 receptor in the ventromedial hypothalamus reduces short-term food intake in male mice by regulating nutrient sensor activity.

Am J Physiol Endocrinol Metab 2017 12 15;313(6):E651-E662. Epub 2017 Aug 15.

Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, Florida.

Pharmacological activation of the glucagon-like peptide-1 receptor (GLP-1R) in the ventromedial hypothalamus (VMH) reduces food intake. Here, we assessed whether suppression of food intake by GLP-1R agonists (GLP-1RA) in this region is dependent on AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR). We found that pharmacological inhibition of glycolysis, and thus activation of AMPK, in the VMH attenuates the anorectic effect of the GLP-1R agonist exendin-4 (Ex4), indicating that glucose metabolism and inhibition of AMPK are both required for this effect. Furthermore, we found that Ex4-mediated anorexia in the VMH involved mTOR but not acetyl-CoA carboxylase, two downstream targets of AMPK. We support this by showing that Ex4 activates mTOR signaling in the VMH and Chinese hamster ovary (CHO)-K1 cells. In contrast to the clear acute pharmacological impact of the these receptors on food intake, knockdown of the VMH conferred no changes in energy balance in either chow- or high-fat-diet-fed mice, and the acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA were preserved. These results show that the VMH GLP-1R regulates food intake by engaging key nutrient sensors but is dispensable for the effects of GLP-1RA on nutrient homeostasis.
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http://dx.doi.org/10.1152/ajpendo.00113.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109646PMC
December 2017

The endogenous preproglucagon system is not essential for gut growth homeostasis in mice.

Mol Metab 2017 07 27;6(7):681-692. Epub 2017 Apr 27.

Gubra Aps, Hørsholm Kongevej 11B, DK-2970 Hørsholm, Denmark.

Objective: The prevalence of obesity and related co-morbidities is reaching pandemic proportions. Today, the most effective obesity treatments are glucagon-like peptide 1 (GLP-1) analogs and bariatric surgery. Interestingly, both intervention paradigms have been associated with adaptive growth responses in the gut; however, intestinotrophic mechanisms associated with or secondary to medical or surgical obesity therapies are poorly understood. Therefore, the objective of this study was to assess the local basal endogenous and pharmacological intestinotrophic effects of glucagon-like peptides and bariatric surgery in mice.

Methods: We used in situ hybridization to provide a detailed and comparative anatomical map of the local distribution of GLP-1 receptor (), GLP-2 receptor (), and preproglucagon () mRNA expression throughout the mouse gastrointestinal tract. Gut development in GLP-1R-, GLP-2R-, or GCG-deficient mice was compared to their corresponding wild-type controls, and intestinotrophic effects of GLP-1 and GLP-2 analogs were assessed in wild-type mice. Lastly, gut volume was determined in a mouse model of vertical sleeve gastrectomy (VSG).

Results: Comparison of , , and mRNA expression indicated a widespread, but distinct, distribution of these three transcripts throughout all compartments of the mouse gastrointestinal tract. While mice null for or showed normal intestinal morphology, mice exhibited a slight reduction in small intestinal mucosa volume. Pharmacological treatment with GLP-1 and GLP-2 analogs significantly increased gut volume. In contrast, VSG surgery had no effect on intestinal morphology.

Conclusion: The present study indicates that the endogenous preproglucagon system, exemplified by the entire GCG gene and the receptors for GLP-1 and GLP-2, does not play a major role in normal gut development in the mouse. Furthermore, elevation in local intestinal and circulating levels of GLP-1 and GLP-2 achieved after VSG has limited impact on intestinal morphometry. Hence, although exogenous treatment with GLP-1 and GLP-2 analogs enhances gut growth, the contributions of endogenously-secreted GLP-1 and GLP-2 to gut growth may be more modest and highly context-dependent.
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http://dx.doi.org/10.1016/j.molmet.2017.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5485241PMC
July 2017

Endocrine Function after Bariatric Surgery.

Compr Physiol 2017 06 18;7(3):783-798. Epub 2017 Jun 18.

Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.

Obesity increases the risks of metabolic disorders including type 2 diabetes mellitus (T2DM). Bariatric surgery is the most successful therapeutic option that causes sustained weight loss and improvements in obesity comorbidities. Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are two of the most frequently performed bariatric surgeries. Despite their different anatomical rearrangement, they have remarkably similar success in both weight loss and T2DM remission. Interestingly, they also both cause a wide range of endocrine changes. Many of these endocrine changes are reflected specifically within the intestine and are implicated as mechanisms for the metabolic success of surgery. However, while most of the work shows that these hormonal changes are associated with the metabolic changes after surgery, causation has been difficult to ascertain. Here, we review the endocrine changes after RYGB and VSG and explore their mechanistic role in the success of bariatric surgery. Further, we explore important changes in gastrointestinal function and the role of these changes in the increase in postprandial endocrine responses after bariatric surgery. © 2017 American Physiological Society. Compr Physiol 7:783-798, 2017.
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http://dx.doi.org/10.1002/cphy.c160019DOI Listing
June 2017

Hypothalamic growth hormone receptor (GHR) controls hepatic glucose production in nutrient-sensing leptin receptor (LepRb) expressing neurons.

Mol Metab 2017 05 16;6(5):393-405. Epub 2017 Mar 16.

Division of Geriatric and Palliative Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address:

Objective: The GH/IGF-1 axis has important roles in growth and metabolism. GH and GH receptor (GHR) are active in the central nervous system (CNS) and are crucial in regulating several aspects of metabolism. In the hypothalamus, there is a high abundance of GH-responsive cells, but the role of GH signaling in hypothalamic neurons is unknown. Previous work has demonstrated that the gene is highly expressed in LepRb neurons. Given that leptin is a key regulator of energy balance by acting on leptin receptor (LepRb)-expressing neurons, we tested the hypothesis that LepRb neurons represent an important site for GHR signaling to control body homeostasis.

Methods: To determine the importance of GHR signaling in LepRb neurons, we utilized Cre/loxP technology to ablate GHR expression in LepRb neurons (Lepr). The mice were generated by crossing the Lepr on the cre-inducible ROSA26-EYFP mice to GHR mice. Parameters of body composition and glucose homeostasis were evaluated.

Results: Our results demonstrate that the sites with GHR and LepRb co-expression include ARH, DMH, and LHA neurons. Leptin action was not altered in Lepr mice; however, GH-induced pStat5-IR in LepRb neurons was significantly reduced in these mice. Serum IGF-1 and GH levels were unaltered, and we found no evidence that GHR signaling regulates food intake and body weight in LepRb neurons. In contrast, diminished GHR signaling in LepRb neurons impaired hepatic insulin sensitivity and peripheral lipid metabolism. This was paralleled with a failure to suppress expression of the gluconeogenic genes and impaired hepatic insulin signaling in Lepr mice.

Conclusion: These findings suggest the existence of GHR-leptin neurocircuitry that plays an important role in the GHR-mediated regulation of glucose metabolism irrespective of feeding.
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http://dx.doi.org/10.1016/j.molmet.2017.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404104PMC
May 2017

Weight loss independent changes in adipose tissue macrophage and T cell populations after sleeve gastrectomy in mice.

Mol Metab 2017 04 16;6(4):317-326. Epub 2017 Feb 16.

Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA. Electronic address:

Objective: In addition to adipocytes, adipose tissue contains large numbers of immune cells. A wide range of evidence links the activity of these cells to regulation of adipocyte and systemic metabolic function. Bariatric surgery improves several aspects of metabolic derangements and at least some of these effects occur in a weight-loss independent manner. We sought to investigate the impact of vertical sleeve gastrectomy (VSG) on adipose immune cell frequencies.

Methods: We analyzed the frequencies of immune cells within distinct adipose tissue depots in obese mice that had VSG or sham surgery with a portion of the latter group pair-fed such that their body mass was matched to the VSG animals.

Results: We demonstrate that VSG induced a shift in the epididymal adipose tissue leukocyte profile including increased frequencies of CD11c macrophages, increased frequencies of T cells (CD4, CD8, and CD4/CD8 T cells all increased), but a significantly decreased frequency of adipose tissue dendritic cells (ATDC) that, despite the continued high fat feeding of the VSG group, dropped below control diet levels.

Conclusions: These results indicate that VSG induces substantial changes in the immune populations residing in the adipose depots independent of weight loss.
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http://dx.doi.org/10.1016/j.molmet.2017.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369283PMC
April 2017

The Role of Pancreatic Preproglucagon in Glucose Homeostasis in Mice.

Cell Metab 2017 Apr 16;25(4):927-934.e3. Epub 2017 Mar 16.

Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

Glucagon-like peptide 1 (GLP-1) is necessary for normal gluco-regulation, and it has been widely presumed that this function reflects the actions of GLP-1 released from enteroendocrine L cells. To test the relative importance of intestinal versus pancreatic sources of GLP-1 for physiological regulation of glucose, we administered a GLP-1R antagonist, exendin-[9-39] (Ex9), to mice with tissue-specific reactivation of the preproglucagon gene (Gcg). Ex9 impaired glucose tolerance in wild-type mice but had no impact on Gcg-null or GLP-1R KO mice, suggesting that Ex9 is a true and specific GLP-1R antagonist. Unexpectedly, Ex-9 had no effect on blood glucose in mice with restoration of intestinal Gcg. In contrast, pancreatic reactivation of Gcg fully restored the effect of Ex9 to impair both oral and i.p. glucose tolerance. These findings suggest an alternative model whereby islet GLP-1 also plays an important role in regulating glucose homeostasis.
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http://dx.doi.org/10.1016/j.cmet.2017.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385998PMC
April 2017

Physiology: Gut feeling for food choice.

Nature 2017 02 8;542(7641):302-303. Epub 2017 Feb 8.

Departments of Surgery, Internal Medicine and Nutritional Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA.

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http://dx.doi.org/10.1038/nature21499DOI Listing
February 2017

Bariatric surgery emphasizes biological sex differences in rodent hepatic lipid handling.

Biol Sex Differ 2017 28;8. Epub 2017 Jan 28.

Department of Surgery, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109 USA.

Background: Eighty percent of patients who receive bariatric surgery are women, yet the majority of preclinical studies are in male rodents. Because sex differences drive hepatic gene expression and overall lipid metabolism, we sought to determine whether sex differences were also apparent in these endpoints in response to bariatric surgery.

Methods: Two cohorts of age-matched virgin male and female Long-Evans rats were placed on a high fat diet for 3 weeks and then received either Sham or vertical sleeve gastrectomy (VSG), a surgery which resects 80% of the stomach with no intestinal rearrangement.

Results: Each sex exhibited significantly decreased body weight due to a reduction in fat mass relative to Sham controls ( < 0.05). Microarray and follow-up qPCR on liver revealed striking sex differences in gene expression after VSG that reflected a down-regulation of hepatic lipid metabolism and an up-regulation of hepatic inflammatory pathways in females vs. males after VSG. While the males had a significant reduction in hepatic lipids after VSG, there was no reduction in females. -fed and fasting circulating triglycerides, and postprandial chylomicron production were significantly lower in VSG relative to Sham animals of both sexes ( < 0.01). However, hepatic VLDL production, highest in sham-operated females, was significantly reduced by VSG in females but not males.

Conclusions: Taken together, although both males and females lose weight and improve plasma lipids, there are large-scale sex differences in hepatic gene expression and consequently hepatic lipid metabolism after VSG.
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http://dx.doi.org/10.1186/s13293-017-0126-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5273842PMC
June 2018

The Physiology and Molecular Underpinnings of the Effects of Bariatric Surgery on Obesity and Diabetes.

Annu Rev Physiol 2017 02 28;79:313-334. Epub 2016 Nov 28.

Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109; email:

Bariatric surgeries, such as Roux-en-Y gastric bypass and vertical sleeve gastrectomy, produce significant and durable weight loss in both humans and rodents. Recently, these surgical interventions have also been termed metabolic surgery because they result in profound metabolic improvements that often surpass the expected improvement due to body weight loss alone. In this review we focus on the weight-loss independent effects of bariatric surgery, which encompass energy expenditure and macronutrient preference, the luminal composition of the gut (i.e., the microbiota and bile acids), the transformation of the gastrointestinal lining, increases in postprandial gut hormone secretions, glycemic control, pancreas morphology, and micronutrient and mineral absorption. Taken together, these data point to several important physiological changes that contribute to the profound benefits of these surgical procedures. Identifying the underlying molecular mechanisms for these physiological effects will allow better utilization of these existing procedures to help patients and develop new treatments that harness these surgical effects with less invasive interventions.
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http://dx.doi.org/10.1146/annurev-physiol-022516-034423DOI Listing
February 2017

The Hypothalamic Glucagon-Like Peptide 1 Receptor Is Sufficient but Not Necessary for the Regulation of Energy Balance and Glucose Homeostasis in Mice.

Diabetes 2017 02 1;66(2):372-384. Epub 2016 Dec 1.

Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL.

Pharmacological activation of the hypothalamic glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) promotes weight loss and improves glucose tolerance. This demonstrates that the hypothalamic GLP-1R is sufficient but does not show whether it is necessary for the effects of exogenous GLP-1R agonists (GLP-1RA) or endogenous GLP-1 on these parameters. To address this, we crossed mice harboring floxed Glp1r alleles to mice expressing Nkx2.1-Cre to knock down Glp1r expression throughout the hypothalamus (GLP-1RKD). We also generated mice lacking Glp1r expression specifically in two GLP-1RA-responsive hypothalamic feeding nuclei/cell types, the paraventricular nucleus (GLP-1RKD) and proopiomelanocortin neurons (GLP-1RKD). Chow-fed GLP-1RKD mice exhibited increased food intake and energy expenditure with no net effect on body weight. When fed a high-fat diet, these mice exhibited normal food intake but elevated energy expenditure, yielding reduced weight gain. None of these phenotypes were observed in GLP-1RKD and GLP-1RKD mice. The acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA exendin-4 and liraglutide were preserved in all mouse lines. Chronic liraglutide treatment reduced body weight in chow-fed GLP-1RKD mice, but this effect was attenuated with high-fat diet feeding. In sum, classic homeostatic control regions are sufficient but not individually necessary for the effects of GLP-1RA on nutrient homeostasis.
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http://dx.doi.org/10.2337/db16-1102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5248999PMC
February 2017