Diego Perez-Tilve

Diego Perez-Tilve
University of Cincinnati | UC · Department of Internal Medicine

PhD

About

148
Publications
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Publications

Publications (148)
Article
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Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links...
Article
Full-text available
Objective: Pharmacological strategies that engage multiple mechanisms-of-action have demonstrated synergistic benefits for metabolic disease in preclinical models. One approach, concurrent glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon (Gcg) receptor activation (i.e. tri-agonism), combines the anorect...
Preprint
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Dual-agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPAR𝛼/𝛾) have shown beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to unfavorable cardiovascular and/or renal effects. Here we report the design and preclinical evaluation of a mo...
Article
Objectives: The control of energy balance relies on the counterbalancing release of neuropeptides encoded by the pro-opiomelanocortin (Pomc) and agouti-related protein (Agrp) genes, expressed by 2 distinct neuronal populations of the arcuate (ARC) nucleus of the hypothalamus. Although largely segregated, single-cell resolution techniques demonstra...
Article
Antagonism of glucagon's biological action is a proven strategy for decreasing glucose in diabetic animals and patients. To achieve full, potent, and selective suppression, we chemically optimized N-terminally truncated glucagon fragments for the identification and establishment of the minimum sequence peptide, [Glu9]glucagon(6-29) amide (11) as a...
Article
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CNS-Gipr KO mice are protected from diet-induced obesity and glucose intolerance d Acyl-GIP increases cFOS neuronal activity in key hypothalamic feeding centers d Acyl-GIP effects on body weight and food intake are absent/ blunted in CNS-mGipr KO mice d GLP-1/GIP dual-agonism loses superior potency over GLP-1 in CNS-mGipr KO mice. In Brief Zhang et...
Article
GLP-1 receptor (GLP-1R) agonists effectively improve glycemia and body weight in patients with type 2 diabetes and obesity, but have limited weight-lowering efficacy and minimal insulin sensitizing action. In preclinical models, peripherally-restricted cannabinoid-1 receptor (CB1R) inhibitors, which are devoid of the neuropsychiatric side-effects o...
Article
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Fibroblast Growth Factors 19 and 21 (FGF19 and FGF21) have biological actions that render them promising clinical candidates for treatment of metabolic diseases, particularly dyslipidemia and nonalcoholic steatohepatitis (NASH). These two atypical endocrine FGFs employ an accessory receptor β-Klotho (KLB) to signal through classical FGF receptors (...
Article
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Objective Recent decades have seen a marked increase in the prevalence of obesity and its associated comorbidities. This increase correlates with greater access to calorie-dense food that is often consumed later in the active phase of the day. Studies in high-fat diet-induced obese (DIO) mice indicate that restricting food access to their active (d...
Article
Native insulin is susceptible to biophysical aggregation and fibril formation, promoted by manual agitation and elevated temperatures. The safety of the drug and its application to alternative forms of administration could be enhanced through identification of chemical modifications that strengthen its physical stability without compromising its bi...
Article
The continued global growth in the prevalence of obesity coupled with the limited number of efficacious and safe treatment options elevates the importance of innovative pharmaceutical approaches. Combinatorial strategies that harness the metabolic benefits of multiple hormonal mechanisms have emerged at the preclinical and more recently clinical st...
Article
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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...
Article
Insulin is the principal hormone involved in the regulation of metabolism and has served a seminal role in the treatment of diabetes. Building upon advances in insulin synthetic methodology, we have developed a straight-forward route to novel insulins containing a fourth disulfide bond in a [3+1] fashion establishing the first disulfide scan of the...
Article
Insulin-like peptide 5 (INSL5) is a member of the insulin-like family of peptides. It has been reported to be orexigenic in rodent models of obesity with impaired glucose metabolism. We attempted to confirm this property as a first step in establishing the ability of INSL5 to successfully integrate with other agents more proven in their ability to...
Article
Full-text available
The melanocortin system is a brain circuit that influences energy balance by regulating energy intake and expenditure. In addition, the brain-melanocortin system controls adipose tissue metabolism to optimize fuel mobilization and storage. Specifically, increased brain-melanocortin signaling or negative energy balance promotes lipid mobilization by...
Article
Leptin promotes adequate caloric intake and glycemia in healthy lean individuals, harnessing the benefits of the ideal therapy against metabolic syndrome. Yet, new evidence demonstrates an unexpected causal role for leptin in obesity-associated hyperglycemia. Like the betrayal of Julius Caesar by Brutus, insulin did not see that coming from leptin.
Article
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Peptides and small proteins are attractive therapeutic candidates due to their inherent selectivity and limited off-target effects. Unfortunately, their potential is often hindered by unfavorable physicochemical properties. This is particularly true in the case of glucagon, a peptide indispensable in the treatment of life-threatening hypoglycemia....
Article
Full-text available
Objective Structurally-improved GIP analogs were developed to determine precisely whether GIP receptor (GIPR) agonism or antagonism lowers body weight in obese mice. Methods A series of peptide-based GIP analogs, including structurally diverse agonists and a long-acting antagonist, were generated and characterized in vitro using functional assays...
Article
Full-text available
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...
Data
Supplemental Figure 1 (refers to main refers to Figures 2B, 4B, 4G): Effect of tamoxifen-induced disruption of Gcgr expression in AKT, pAKT and beta actin protein content in the liver. (a) Ratio pAKT/total AKT. (b) Inmunoblot film used for densitometry quantification. Data are presented as mean ± SEM. n = 6. *P < 0.05, t-test. Supplemental Figure 2...
Article
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Objective: Mice with congenital loss of the glucagon receptor gene (Gcgr-/- mice) remain normoglycemic in insulinopenic conditions, suggesting that unopposed glucagon action is the driving force for hyperglycemia in Type-1 Diabetes Mellitus (T1DM). However, chronic loss of GCGR results in a neomorphic phenotype that includes hormonal signals with...
Article
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Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss, in part through potentiation of fibroblast-growth factor 21 (FGF21) secretion. However, FGF21 is only a partial mediator of metabolic actions ensuing from GcgR-activation, prompting us to search for additional pathways. Intriguingly, chronic GcgR agonism in...
Article
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Exposure to cold temperature is well known to upregulate heat shock protein (Hsp) expression and recruit and/or activate brown adipose tissue and beige adipocytes in humans and animals. However, whether and how Hsps regulate adipocyte function for energy homeostatic responses is poorly understood. Here, we demonstrate a critical role of Hsp20 as a...
Article
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Objective: To signal, FGF19 and FGF21 require co-receptor βKlotho (KLB) to act in concert with FGF receptors, and yet there is appreciable variance in the C-terminal sequences of these two novel metabolic hormones where binding is believed to be primary. We seek to determine the functional consequences for these amino acid differences and determin...
Data
Figure S1. C-terminal FGF peptides dose-dependently antagonize FGF19 and FGF21 activity in 293/KLB cells. (A) Antagonism of FGF21 by 19C26 (blue), 19C25 (black) and 19C26,ΔT14 (red); (B) antagonism of FGF19 by FGF2118−181 (black), 21C25 (red), 19C26 (blue) and 19C26,A26 (green). The graphs show representative curves plotted by normalizing the pERK...
Data
Table S1. Nomenclature for FGF protein and C-terminal peptide analogs. Table S2. Receptor binding of C-terminal FGF21 Ala-scan peptides. IC50 values (μM, mean, n = 2) with fold-change for 21C25 Ala-scan peptides versus native peptide in a cell free AlphaScreen binding assay where the 21C25 Ala peptides competed with FGF21 to associate with the huma...
Article
Ghrelin is a 28-amino acid polypeptide that regulates feeding, glucose metabolism and emotionality (stress, anxiety and depression). Plasma ghrelin circulates as desacyl ghrelin (DAG) or in an acylated form, acyl ghrelin (AG), through the actions of Ghrelin -O-Acyltransferase (GOAT), exhibiting low or high affinity, respectively, for the growth hor...
Article
In response to an acute threat to homeostasis or well-being, the hypothalamic-pituitary-adrenocortical (HPA) axis is engaged. A major outcome of this HPA axis activation is the mobilization of stored energy, to fuel an appropriate behavioral and/ or physiological response to the perceived threat. Importantly, the extent of HPA axis activity is thou...
Article
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...
Article
The incidence of obesity, with its impact on the development of comorbidities including diabetes and cardiovascular disease, represents one of the greatest global health threats of the 21st century. This is particularly damning considering the vast progress that has been made in understanding the factors and molecular mechanisms playing a role in t...
Article
Peptide-based therapeutics commonly suffer from biophysical properties that compromise pharmacology and medicinal use. Structural optimization of the primary sequence is the usual route to address such challenges while trying to maintain as much native character, and avoiding introduction of any foreign element that might evoke an immunological res...
Article
Glucagon and thyroid hormone (T3) exhibit therapeutic potential for metabolic disease but also exhibit undesired effects. We achieved synergistic effects of these two hormones and mitigation of their adverse effects by engineering chemical conjugates enabling delivery of both activities within one precisely targeted molecule. Coordinated glucagon a...
Article
Glucagon (GCG) 1 serves a seminal physiological role in buffering against hypoglycemia, but its poor biophysical properties severely complicate its medicinal use. We report a series of novel glucagon analogs of enhanced aqueous solubility and stability at neutral pH, anchored by [Aib16] GCG(1-29). Incorporation of 3- and 4-Pyridyl-alanine (3-Pal an...
Article
Full-text available
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...
Article
Many complex diseases have historically proven to be defiant to the best mono-therapeutic approaches. Several examples of combination therapies have largely overcome such challenges, notably for the treatment of severe hypertension and tuberculosis. Obesity and its consequences, such as type 2 diabetes, have proven to be equally resistant to therap...
Article
Full-text available
Objective: Fibroblast activation protein (FAP) is a serine protease belonging to a S9B prolyl oligopeptidase subfamily. This enzyme has been implicated in cancer development and recently reported to regulate degradation of FGF21, a potent metabolic hormone. Using a known FAP inhibitor, talabostat (TB), we explored the impact of FAP inhibition on me...
Article
Glucagon-like peptide-1 (GLP-1) analogs are considered the best current medicines for type 2 diabetes (T2D) and obesity due to their actions in lowering blood glucose and body weight. Despite similarities to GLP-1, glucose-dependent insulinotropic polypeptide (GIP) has not been extensively pursued as a medical treatment for T2D. This is largely bas...
Article
Full-text available
Hypothalamic leptin signalling has a key role in food intake and energy-balance control and is often impaired in obese individuals. Here we identify histone deacetylase 5 (HDAC5) as a regulator of leptin signalling and organismal energy balance. Global HDAC5 KO mice have increased food intake and greater diet-induced obesity when fed high-fat diet....
Data
Supplementary Figures 1-9 and Supplementary Tables 1-4
Article
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Objective: Type 2 diabetes and obesity are emerging pandemics in the 21st century creating worldwide urgency for the development of novel and safe therapies. We investigated trace amine-associated receptor 1 (TAAR1) as a novel target contributing to the control of glucose homeostasis and body weight. Methods: We investigated the peripheral human...
Data
Immunohistochemistry experiments on human tissue sections revealed that TAAR1 is not broadly expressed. For each assessment, tissue sections from 3 independent healthy donors were stained for TAAR1 expression using anti-hTaar1 mAb. Staining was performed using AEC-red as substrate for peroxidase conjugated secondary antibody. No TAAR1 expression wa...
Article
Full-text available
Canonical protein phosphatase 3/calcineurin signaling is central to numerous physiological processes. Here we provide evidence that calcineurin plays a pivotal role in controlling systemic energy and body weight homeostasis. Knockdown of calcineurin in Drosophila melanogaster led to a decrease in body weight and energy stores, and increased energy...
Article
Full-text available
We assessed the contribution of glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) signalling to thermogenesis induced by high-fat diet (HFD) consumption. Furthermore, we determined whether brown adipose tissue (BAT) activity contributes to weight loss induced by chronic subcutaneous treatment with the GLP-1R agonist, liraglutide, in a model of diet...
Article
Obesity is characterized by hyperleptinemia and decreased response to exogenous leptin. This has been widely attributed to the development of leptin resistance, a state of impaired leptin signaling proposed to contribute to the development and persistence of obesity. To directly determine endogenous leptin activity in obesity, we treated lean and o...
Article
Full-text available
Glucagon-like peptide-1 (GLP-1) enhances meal-related insulin secretion, which lowers blood glucose excursions. In addition to its incretin action, GLP-1 acts on the GLP-1 receptor (GLP-1R) in the brain to suppress feeding. These combined actions of GLP-1R signaling cause improvements in glycemic control as well as weight loss in type II diabetes (...
Article
Full-text available
Ghrelin is a circulating hormone that targets the central nervous system (CNS) to regulate feeding and adiposity. The best-characterized neural system that mediates the effects of ghrelin on energy balance involves the activation of neuropeptide Y/ agouti-related peptide (NPY/AGRP) neurons, expressed exclusively in the arcuate (ARC) nucleus of the...
Article
Full-text available
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...
Article
Background: The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. Scope of review: In this review, we discuss the divers...
Article
Full-text available
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...
Article
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...
Article
The arcuate nucleus (ARC) of the hypothalamus plays a key role in sensing metabolic feedback and regulating energy homeostasis. Recent studies revealed activation of microglia in mice with high-fat diet (HFD)-induced obesity (DIO), suggesting a potential pathophysiological role for inflammatory processes within the hypothalamus. To further investig...
Chapter
Ghrelin is the only known circulating hormone with strong orexigenic activity. No other peripheral endocrine agent has comparable effects on hunger and energy balance. Although the first evidence of the contribution of ghrelin to the control of food intake was obtained soon after its discovery, the precise mechanisms whereby ghrelin regulates feedi...
Article
Full-text available
Several bariatric operations are currently used to treat obesity and obesity-related comorbidities. These vary in efficacy, but most are more effective than current pharmaceutical treatments. Roux-en-Y Gastric Bypass (RYGB) produces substantial body weight (BW) loss, enhanced glucose tolerance, and is associated with increased secretion of the gut...