Darleen A Sandoval

• Ph.D.
• Professor (Assistant) at University of Michigan

Several discrete groups of feeding-regulated neurons in the nucleus of the solitary tract ( nucleus tractus solitarius ; NTS) suppress food intake, including avoidance-promoting neurons that express Cck (NTS Cck cells) and distinct Lepr - and Calcr -expressing neurons (NTS Lepr and NTS Calcr cells, respectively) that suppress food intake without pr...

Nearly 80% of patients that receive bariatric surgery are women, yet mechanistic pre-clinical studies have focused on males. The goal of this study was to determine the metabolic impact of diet- and surgery-induced weight loss in males, females, and ovariectomized females. Male and female mice were fed a 60% high-fat (HFD) diet before undergoing ei...

Leptin is a potent endocrine hormone produced by adipose tissue and regulates a broad range of whole-body metabolism such as glucose and lipid metabolism, even without insulin. Central leptin signaling can lower hyperglycemia in insulin-deficient rodents via multiple mechanisms, including improvements of dyslipidemia. However, the specific neurons...

Leptin receptor (LepRb)-expressing neurons of the nucleus tractus solitarius (NTS; LepRbNTS neurons) receive gut signals that synergize with leptin action to suppress food intake. NTS neurons that express preproglucagon (Ppg) (and which produce the food intake-suppressing PPG cleavage product, glucagon-like peptide-1 (GLP1)) represent a subpopulati...

Leptin is a potent endocrine hormone produced by adipose tissue and regulates a broad range of metabolism including glucose and lipid metabolism, with and without insulin. It is evident that central leptin signaling can lower hyperglycemia in insulin-deficient rodents via multiple mechanisms including restoration of dyslipidemia. However, the speci...

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...

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 (CCK) receptor-B (CCKBR)-expressing VMN targets of glucose-elevating parabrachial nucleus neurons. Activating these VMNCCKBR neurons increased blood glucose. Furt...

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 CalcrNTS neurons decreased food intake and body weigh...

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. While the mechanism behind bromocriptine's effect on glucose intolerance is unclear, here we test three hypotheses: that bromocriptine may exert i...

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...

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 th...

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...

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 ob...

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 improv...

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...

Background: The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell prol...

Sepsis is characterized by a dysregulated immune response that can result in end organ damage and is the number one cause of death in the ICU. Among the hormones that are altered by sepsis, there is an increase in the gut peptide glucagon-like peptide-1 (GLP-1). Traditionally, GLP-1 is important for regulating glucose homeostasis and has previously...

The diabetes community has long desired an imaging agent to quantify the number of insulin-secreting beta (β) cells, beyond just functional equivalents (insulin secretion), to help diagnose and monitor early stages of both type 1 and type 2 diabetes mellitus. Loss in the number of β-cells can be masked by a compensatory increase in function of the...

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...

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...

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...

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 followin...

Glucagon receptor (GCGR) agonists cause hyperglycemia but also weight loss. However, GLP1R/GCGR mixed agonists do not exhibit the diabetogenic effects often attributed to GCGR activity. Thus, we sought to investigate the effect of glucagon agonism on insulin action and glucose homeostasis. Acute GCGR agonism induced immediate hyperglycemia, followe...

Glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved weight loss drugs. Despite their widespread use, the sites of action through which GLP-1R agonists (GLP1RAs) impact appetite and body weight are still not fully understood. Here, we determined whether GLP-1Rs in either GABAergic or glutamatergic neurons are necessary for the acute...

While the goal of diabetes treatment is normoglycemia, most therapeutics (especially insulin and insulin secretagogues) carry with them a significant risk of potentially life-threatening hypoglycemia; this risk increases with the intensity of therapy. While neurons of the ventromedial hypothalamic nucleus (VMN) play an essential role in the CRR, th...

Glucagon-like peptide-1 (GLP-1) is a gut peptide that increases post prandially and functions to increase insulin secretion and improve glucose homeostasis. GLP-1 is coded by the preproglucagon gene (Gcg) and is expressed by intestinal and pancreatic cells. Interestingly, GLP-1 is also increased during sepsis, which is the most common cause of deat...

Despite the well-known efficacy of bariatric surgery in reducing body mass and improving metabolic outcomes, the mechanisms underlying these dramatic effects are not fully understood. Nearly 80% of patients that receive bariatric surgery are women, yet mechanistic pre-clinical studies have focused exclusively on males. Premenopausal women have a re...

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 home...

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 intrins...

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 of the most popular bariatric procedures, vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB), are commonly considered ‘metabolic surgeries’ because they are thought to impact metabolism in a weight loss-independent manner. In support of this, improvements in glucose homeostasis, insulin sensitivity, and even discontinuation o...

Chronic inflammation has been proposed to contribute to the pathogenesis of diet-induced obesity. However, scarce therapeutic options are available to treat obesity and the associated immunometabolic complications. Glucocorticoids are routinely employed for the management of inflammatory diseases, but their pleiotropic nature leads to detrimental m...

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 upon AMP-activated protein kinase (AMPK) and mammalian Target of Rapamycin (mTOR). We found that pharmac...

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 bariatri...

Introduction Sleep apnea is highly correlated with obesity and neck circumference. This observation has led many to conclude that the physical weight of fat around the airway leads to restriction and apnea. However, recent evidence implicates obesity-related physiology, including the role of leptin, in the pathogenesis of sleep apnea. Here we deter...

The glucagon-like peptide 1 (GLP-1) system plays an important role in blood glucose regulation, in great part through coordinate control of insulin and glucagon secretion. These effects are generally attributed to GLP-1 produced in peripheral sites, principally the intestine. GLP-1 is also produced in hindbrain neurons that signal through GLP-1 rec...

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 mechani...

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 w...

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 antagonis...

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. Previou...

One effect of weight-loss surgery is a change in food preferences. An analysis in rats shows that this is caused by altered nutrient signals in the intestine. These activate the vagus nerve to increase signalling in the brain by the neurotransmitter dopamine.

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...

Glucagon is predominantly made in islet α cells and regulates systemic glycemia primarily through actions in the liver. Beyond endocrine actions in glucose counter-regulation and metabolism of protein rich meals, glucagon may have roles in paracrine regulation of islet function and energy balance. Excess glucagon contributes to dysglycemia in perso...

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. T...

Bariatric surgery is currently the most effective treatment for obesity and associated comorbidities, including rapid resolution of type 2 diabetes mellitus (T2DM). Although the weight loss itself has substantial impact, bariatric surgery also has weight loss?independent effects on T2DM. Several variations of bariatric surgery exist, including the...

Exercise is an effective therapy against the metabolic syndrome. However, the molecular pathways underlying the advantageous effects of exercise are elusive. Glucagon receptor signaling is essential for exercise benefits, and recent evidence indicates that a downstream effector of glucagon, fibroblast growth factor 21 (FGF21), is implicated in this...

A recent study has shown that a single dose of fibroblast growth factor (FGF) 1 into the central nervous system (CNS) of various mouse and rat models of type 2 diabetes results in profound and exceptionally long-lasting reductions in blood glucose. This work raises the possibility of truly revolutionary therapies for individuals with type 2 diabete...

Bariatric surgery is currently the most effective treatment for obesity. Not only do these types of surgeries produce significant weight loss but also they improve insulin sensitivity and whole body metabolic function. The aim of this review is to explore how altered physiology of adipose tissue may contribute to the potent metabolic effects of som...

Despite clear associations between vitamin D deficiency and obesity and/or type 2 diabetes, a causal relationship is not established. Vitamin D receptors (VDR) are found within multiple tissues, including the brain. Given the importance of the brain in controlling both glucose levels and body weight, we hypothesized that activation of central VDR l...

Background: Prader-Willi syndrome (PWS) is a genetic disorder characterized by hyperphagia, obesity, cardiopulmonary diseases, and increased mortality. Although successful weight loss improves health in PWS, few treatments cause sustained weight loss in obese patients let alone obese individuals with PWS. Objectives: The present study uses the M...

Objective: Melanocortin-4 receptors (MC4Rs) are highly expressed by dopamine-secreting neurons of the mesolimbic tract, but their functional role has not been fully resolved. Voluntary wheel running (VWR) induces adaptations in the mesolimbic dopamine system and has a myriad of long-term beneficial effects on health. In the present experiments we...

Bariatric surgery is the most effective and durable treatment option for obesity today. More importantly, beyond weight loss, bariatric procedures have many advantageous metabolic effects including reversal of obesity-related liver disease - nonalcoholic steatohepatitis (NASH). NASH is an important comorbidity of obesity given that it is a precurso...

Mounting evidence supports a link between circadian disruption and metabolic disease. Humans with circadian disruption (e.g., night-shift workers) have an increased risk of obesity and cardiometabolic diseases compared to the non-disrupted population. However, it is unclear if the obesity and obesity-related disorders associated with circadian disr...

The preproglucagon gene (Gcg) is expressed by specific enteroendocrine cells (L-cells) of the intestinal mucosa, pancreatic islet α-cells, and a discrete set of neurons within the nucleus of the solitary tract. Gcg encodes multiple peptides including glucagon, glucagon-like peptide-1, glucagon-like peptide-2, oxyntomodulin, and glicentin. Of these,...

The melanocortin system directs diverse physiological functions from coat color to body weight homoeostasis. A commonality among melanocortin-mediated processes is that many animals modulate similar processes on a circannual basis in response to longer, summer days, suggesting an underlying link between circadian biology and the melanocortin system...

Bariatric surgical procedures such as vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) are the most potent treatments available to produce sustained reductions in body weight and improvements in glucose regulation. While traditionally these effects are attributed to mechanical aspects of these procedures, such as restriction an...

Hypoglycemia is a common and dangerous adverse complication of diabetes treatment. In people without diabetes, powerful counterregulatory hormonal responses defend against a falling glucose, but in type 1 diabetes and longer-duration type 2 diabetes these defenses can be impaired or absent. An increased risk of hypoglycemia is associated with previ...

We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. This triple agonist demon...

Obesity is a growing health risk with few successful treatment options and fewer still that target both obesity and obesity-associated comorbidities. Despite ongoing scientific efforts, the most effective treatment option to date was not developed from basic research but by surgeons observing outcomes in the clinic. Bariatric surgery is the most su...

Vertical sleeve gastrectomy (VSG) is currently one of the most effective treatments for obesity. Despite recent developments, the underlying mechanisms that contribute to the metabolic improvements following bariatric surgery remain unresolved. VSG reduces postprandial intestinal triglyceride (TG) production, but whether the effects of VSG on intes...

Bariatric surgery is the most successful strategy for obesity treatment, yet the mechanisms for this success are not clearly understood. Clinical literature suggests that plasma levels of apolipoprotein A-IV (A-IV) rise with roux-en-Y gastric bypass (RYGB). A-IV is secreted from the intestine postprandially and has demonstrated benefits for both gl...

Long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists have both glucose- and weight-lowering effects. The brain is poised to mediate both of these actions since GLP-1Rs are present in key areas known to control weight and glucose. Although some research has been performed on the effects of exendin-4 in the brain, little data exists on the...

Glucagon-like peptide-1 (GLP-1), an insulinotropic gut peptide released after eating, is essential for normal glucose tolerance (GT). To determine whether this effect is mediated directly by GLP-1 receptors (GLP1R) on islet β cells, we developed mice with β cell-specific knockdown of Glp1r. β cell Glp1r knockdown mice had impaired GT after intraper...

Glucose control and weight loss are cornerstones of type 2 diabetes treatment. Currently, only glucagon-like peptide-1 (GLP1) analogs are able to achieve both weight loss and glucose tolerance. Both glucose and body weight are regulated by the brain, which contains GLP1 receptors (GLP1R). Even though the brain is poised to mediate the effects of GL...

Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, des...

The intestinal tract is the first barrier from the external to the internal environment. As such, it plays a key role not only in nutrient absorption but also in protection from toxins and immunity. However, the gut is not alone in this regulatory role. The mammalian intestinal tract is colonized by trillions of microorganisms collectively referred...

Roux-en Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are effective weight loss surgeries that also improve glucose metabolism. Rapid, early rises of circulating insulin and glucagon-like peptide (GLP)-1 concentrations following food ingestion are characteristic of these procedures. The purpose of the current study was to test the h...

Ghrelin receptors (GHSRs) in the central nervous system (CNS) mediate hyperphagia and adiposity induced by acyl ghrelin (AG). Evidence suggests that des-acyl ghrelin (dAG) has biological activity through GHSR independent mechanisms. We combined in vitro and in vivo approaches to test possible GHSR-mediated biological activity of dAG. Both AG (100nM...

Moderate low-carbohydrate/high-fat diets (LC-HFDs) are widely used to induce weight loss in overweight subjects, whereas extreme ketogenic LC-HFDs are used to treat neurological disorders like pediatric epilepsy. Usage of LC-HFD for improvement of glucose metabolism is highly controversial: some studies suggest that LC-HFDs ameliorate glucose toler...

Background: Obesity has a complicated metabolic pathology, and defining the underlying mechanisms of obesity requires integrative studies with molecular end points. Real-time quantitative PCR (RT-qPCR) is a powerful tool that has been widely utilized. However, the importance of using carefully validated reference genes in RT-qPCR seems to have bee...

Background: Increases in L-cell release of GLP-1 are proposed to serve as a negative feedback signal for postprandial changes in gastric emptying and/or motility. Previous ex vivo data suggests that direct electrical stimulation (E-stim) of ileal segments stimulates secretion of GLP-1. This suggests potential feed-forward increases in GLP-1 driven...

Individual meals are products of a complex interaction of signals related to both short-term and long-term availability of energy stores. In addition to maintaining the metabolic demands of the individual in the short term, levels of energy intake must also maintain and defend body weight over longer periods. To accomplish this, satiety pathways ar...

Overconsumption of high-fat diet promotes weight gain that can result in obesity and associated comorbidities, including type 2 diabetes mellitus. Consumption of high-fat diet also alters gut-brain communication. Glucagon-like peptide 1 (GLP-1) is an important gastrointestinal signal that modulates both short- and long-term energy balance and is in...

Over the last 15 years, considerable work has accumulated to support the role of the CNS in regulating postprandial glucose levels. As discussed in the first section of this review, the CNS receives and integrates information from afferent neurons, circulating hormones, and postprandially generated nutrients to subsequently direct changes in glucos...

Glucagon-Like Peptide-1 (GLP-1) is a peptide hormone that is released from the gut in response to nutrient ingestion, and has a range of metabolic effects including enhancing insulin secretion and decreasing food intake. Post-prandial GLP-1 secretion is greatly enhanced in rats and humans following some bariatric procedures, including Vertical Slee...

GLP-1-induced insulin secretion from the β-cell is dependent upon glucose availability. The purpose of the current study was to determine whether CNS GLP-1 signaling is also glucose-dependent. We found that fasting blunted the ability of 3(rd) cerebroventricularly (i3vt)-administered GLP-1 to reduce food intake. However, fasted animals maintained t...

Obesity and type 2 diabetes mellitus (T2DM) - disorders of energy homeostasis and glucose homeostasis, respectively - are tightly linked and the incidences of both conditions are increasing in parallel. The CNS integrates information regarding peripheral nutrient and hormonal changes and processes this information to regulate energy homeostasis. Re...

Reductions in levels of the hunger-stimulating hormone ghrelin have been proposed to mediate part of the effects of vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass surgeries for obesity. We studied circulating levels of acyl and desacyl ghrelin in rats after these surgeries. We found that blood levels of ghrelin were reduced after VS...

Vertical sleeve gastrectomy (VSG) is a restrictive procedure that reduces food intake to produce weight loss. Here we assess volume and nutrient effects on the ingestive behavior of VSG and sham surgery animals. Rats given access to Ensure or pelleted chow were used to determine if liquid foods would adversely affect weight loss after surgery. Volu...

A peptide designed to induce apoptosis of endothelium in white adipose tissue (WAT) decreases adiposity. The goal of this work is to determine whether targeting of WAT endothelium results in impaired glucose regulation as a result of impaired WAT function. Glucose tolerance tests were performed on days 2 and 3 of treatment with vehicle (HF-V) or pr...

Despite considerable scientific progress on the biological systems that regulate energy balance, we have made precious little headway in providing new treatments to curb the obesity epidemic. Diet and exercise are the most popular treatment options for obesity, but rarely are they sufficient to produce long-term weight loss. Bariatric surgery, on t...