Jose Cordoba-Chacon

University of Illinois at Chicago | UIC · Department of Medicine, Division of Endocrinology, Diabetes and Metabolism

Our group has previously reported de novo lipogenesis (DNL) and hepatic triglyceride (TG) content increases in chow-fed male mice within 7 days of hepatocyte-specific growth hormone receptor knockdown (aLivGHRkd). Herein we report that these changes are associated with an increase in hepatic expression of peroxisome proliferator-activated receptor...

Peroxisome proliferator-activated receptor γ (PPARγ) is the target for thiazolidinones (TZDs), drugs that improve insulin sensitivity and fatty liver in humans and rodent models, related to a reduction in hepatic de novo lipogenesis (DNL). The systemic effects of TZDs are in contrast to reports suggesting hepatocyte-specific activation of PPARγ pro...

Thiazolidinediones (TZD) are peroxisome proliferator-activated receptor γ (PPARγ agonists that could reduce hepatic steatosis through their effects in adipose tissue, and therefore have been assessed as potential therapies to treat non-alcoholic fatty liver disease (NAFLD) in humans. However, some studies suggest that expression and activation of h...

Peroxisome proliferator-activated receptor γ (PPARγ) belongs to a family of nuclear receptors that could serve as lipid sensors. PPARγ is the target of a group of insulin sensitizers called thiazolidinediones (TZD) which regulate the expression of genes involved in glucose and lipid metabolism, as well as adipokines that regulate metabolic function...

Non-alcoholic steatohepatitis (NASH) is associated with obesity and increased expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ). However, the relevance of hepatocyte PPARγ in NASH associated with obesity is still poorly understood. In this study, hepatocyte PPARγ was knocked out (PpargΔHep) in male and female mice after the...

Secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is a poorly characterized secreted protein of largely unknown physiological function. Here we demonstrate that scEMC10 is upregulated in people with obesity and is positively associated with insulin resistance. Consistent with a causal role for scEMC10 in obesity, Emc10...

Liver cancer (LC) is the fourth leading cause of death from cancer malignancies. Recently, a putative fifth hexokinase, hexokinase domain containing 1 (HKDC1), was shown to have significant overexpression in LC compared to healthy liver tissue. Using a combination of in vitro and in vivo tools, we examined the role of HKDC1 in LC development and pr...

Background & Aims Non-alcoholic steatohepatitis (NASH) is associated with obesity and increased expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ) in humans. Although we previously showed that the expression of PPARγ in hepatocytes contributes to the development NASH in lean mice, the relevance of hepatocyte PPARγ in the dev...

Hepatocellular carcinoma (HCC) is a leading cause of death from cancer malignancies. Recently, hexokinase domain containing 1 (HKDC1), was shown to have significant overexpression in HCC compared to healthy tissue. Using in vitro and in vivo tools, we examined the role of HKDC1 in HCC progression. Importantly, HKDC1 ablation stops HCC progression b...

We found the hepatic transcription factor Cyclic-AMP Responsive Element Binding Protein 3-like-3 (CREB3L3) to be expressed in adipose tissue, and selectively downregulated in the more metabolically protective subcutaneous adipose tissue in obese mice and humans. We sought to elucidate the specific role of this factor in adipose biology. CREB3L3 fat...

Secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is a poorly characterised secreted protein of largely unknown physiological function. Here we demonstrate that scEMC10 is upregulated in humans with obesity and is positively associated with insulin resistance. Consistent with a causal role for scEMC10 in obesity, Emc10...

Pancreatic cancer (PC) is one of the few cancers for which incidence and mortality continue to rise despite increasing knowledge of its etiology and risk factors. Amongst the latter, dietary patterns are significantly associated with PC risk. Due to its relatively slow progression, preventive strategies represent a simple means to improve outcomes....

Osteoarthritis (OA), the most prevalent joint disease, is a major cause of disability worldwide. Growth hormone (GH) has been suggested to play significant roles in maintaining articular chondrocyte function and ultimately articular cartilage (AC) homeostasis. In humans, the age-associated decline in GH levels was hypothesized to play a role in the...

ECE meeting

A reduction in GH, as well as IGF1, is associated with non-alcoholic fatty liver disease (NAFLD). However, the relative contribution of changes in circulating GH and IGF1, to hepatic triglyceride accumulation (steatosis), remains to be clearly defined. To study the direct actions of GH on hepatocyte metabolism, we have utilized a mouse model of adu...

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of pathologies ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) that can lead to cirrhosis and hepatocellular carcinoma. Clinical and mouse studies indicate GH-signaling is reduced in NAFLD. We reported that chow-fed mice, with adult-onset, hepatocyte-specific GH r...

Background and aims Non-alcoholic steatohepatitis (NASH) is commonly observed in patients with type 2 diabetes, and thiazolidinediones (TZD) are considered a potential therapy for NASH. Although TZD increase insulin sensitivity and partially reduce steatosis and ALT, the efficacy of TZD on resolving liver pathology is limited. In fact, TZD may acti...

A reduction in hepatocyte growth hormone (GH)-signaling promotes non-alcoholic fatty liver disease (NAFLD). However, debate remains as to the relative contribution of the direct effects of GH on hepatocyte function versus indirect effects, via alterations in insulin-like growth factor 1 (IGF1). To isolate the role of hepatocyte GH receptor (GHR) si...

Pparg is a nuclear receptor that regulates glucose and lipid metabolism. Thiazolidinediones (TZD) are PPARG agonists that may reduce hepatic steatosis through their effects in adipose tissue. However, some studies suggest that expression and activation of hepatocyte Pparg promotes steatosis. In this study, we have assessed the relevance of hepatocy...

GH dysregulation contributes to the development of non-alcoholic fatty liver disease (NAFLD), however debate remains as to the relative contribution of the direct vs indirect effects of GH, via IGF1. Mouse models with congenital, liver-specific knockout of the GHR, JAK2 or STAT5, as adults exhibit steatosis, glucose intolerance, insulin resistance...

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. To date, there is not a specific and approved treatment for NAFLD yet, and therefore, it is important to understand the molecular mechanisms that lead to the progression of NAFLD. Methionine- and choline-deficient (MCD) diets are used to reproduce some features of N...

Significance Although activation of PI3K p110α appears to promote pancreatic cancer development via canonical AKT signaling, in the setting of a high-fat diet (enriched in ω−6 fatty acids), unopposed p110γ inhibition poses a risk for severe hepatic damage. Considering that obesity is a risk factor for pancreatic cancer, these observations suggest t...

Hepatic PPARγ expression is positively associated with the progression of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) in mice and humans. Although PPARγ agonists, thiazolidinediones (TZD), could be used to treat patients with NASH, these drugs reduced steatosis only in some patients with NASH, while it exacerbated ste...

Mixtures of the two major conjugated linoleic acid (CLA) isomers trans-10,cis-12-CLA and cis-9,trans-11-CLA are used as over the counter supplements for weight loss. Because of the reported adverse effects of CLA on insulin sensitivity in some mouse studies, we sought to compare the impact of dietary t10c12-CLA and c9t11-CLA on liver, adipose tissu...

Glucokinase (GCK) is the principal hexokinase (HK) in the liver, operating as a glucose sensor to regulate glucose metabolism and lipid homeostasis. Recently, we proposed Hexokinase Domain Containing-1 (HKDC1) to be a novel 5th HK with expression in the liver. Here, we reveal HKDC1 to have low glucose-phosphorylating ability and demonstrate its ass...

Hexokinase domain containing 1, a recently discovered putative fifth hexokinase, is hypothesized to play key roles in glucose metabolism. Specifically, during pregnancy in a recent genome wide association study (GWAS), a strong correlation between HKDC1 and 2-h plasma glucose in pregnant women from different ethnic backgrounds was shown. Our earlie...

Nonalcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis (NASH), is associated with reduced growth hormone (GH) input/signaling and GH therapy is effective in the reduction/resolution of NAFLD/NASH in select patient populations. Our laboratory has focused on isolating the direct vs. indirect effects of GH in preventing...

Pancreatic ductal adenocarcinoma (PDAC) presents a significant challenge clinically, with poor overall survival and widespread resistance to conventional therapies. Several novel molecular targets are being considered in the management of PDAC patients. To this end, as hyperactive PI3K signaling is implicated in both disease incidence and progressi...

Autophagy, a stress-induced lysosomal degradative pathway, has been assumed to exert similar metabolic effects in different organs. Here, we establish a model where autophagy plays different roles in insulin-producing β cells versus insulin-responsive cells, utilizing knockin (Becn1F121A) mice manifesting constitutively active autophagy. With a hig...

Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have low growth hormone (GH) production and/or hepatic GH resistance. GH replacement can resolve the fatty liver condition in diet-induced obese rodents and in GH-deficient patients. However, it remains to be determined whether this inhibitory action of GH is due to direct regul...

Somatostatin (SST) and cortistatin (CORT) regulate numerous endocrine secretions and their absence [knockout (KO)-models] causes important endocrine-metabolic alterations, including pituitary dysregulations. We have demonstrated that the metabolic phenotype of single or combined SST/CORT KO-models is not drastically altered under normal conditions....

In humans low levels of growth hormone (GH) and its mediator, insulin-like growth factor-1 (IGF-1), associate with hepatic lipid accumulation. In mice, congenital liver-specific ablation of the GH receptor (GHR) results in reductions in circulating IGF-1 and hepatic steatosis, associated with systemic insulin-resistance. Due to the intricate relati...

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are essential factors in mammary-gland (MG) development and are altered during fasting. However, no studies have investigated the alterations in the expression of GH/IGF-I and its regulatory systems (somatostatin/cortistatin and ghrelin) in MG during fasting. Therefore, this study was aim...

Cortistatin (CORT) shares high structural and functional similarities with somatostatin, but displays unique sex-dependent pituitary actions. Indeed, whereas female CORT-knockout (CORT-KO) mice exhibit enhanced GH expression/secretion, POMC expression, and circulating ACTH/corticosterone/ghrelin levels, male CORT-KO mice only display increased plas...

Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have low growth hormone (GH) production and/or hepatic GH resistance. GH replacement can resolve fatty liver in diet-induced obese rodents and in GH-deficient patients. However, it remains to be determined if this inhibitory action of GH is due to direct regulation of hepatic li...

Somatostatin (SST) and cortistatin (CORT) are two highly related neuropeptides involved in the regulation of various endocrine secretions. In particular, SST and CORT are two primary negative regulators of growth hormone (GH) secretion. Consequently, single SST- or CORT-knockout mice exhibit elevated GH levels; however, this does not lead to increa...

Locally produced growth hormone (GH) and IGF-I are key factors in the regulation of mammary gland (MG) development and may be important in breast cancer development/progression. Somatostatin (SST) and cortistatin (CORT) regulate GH/IGF-I axis at various levels, but their role in regulating GH/IGF-I in MGs remains unknown. Since obesity alters the e...

Melatonin is secreted by the pineal gland and exhibits a striking circadian rhythm in its release. Depending on the species studied some pituitary hormones also display marked circadian/seasonal patterns and rhythms of secretion. However, the precise relationship between melatonin and pituitary function remains controversial, and studies focusing o...

A reciprocal relationship between insulin sensitivity and glucose tolerance has been reported in some mouse models and humans with isolated changes in GH production and signaling. In order to determine if this could be explained in part by tissue-specific changes in insulin sensitivity, hyperinsulinemic/euglycemic clamps were performed in mice with...

GH and/or IGF-I are thought to promote breast cancer based on reports showing circulating IGF-I levels correlate, in epidemiological studies, with breast cancer risk. Also, mouse models with developmental GH/IGF-I deficiency/resistance are less susceptible to genetic- or chemical-induced mammary tumorigenesis. However, given the metabolic propertie...

Developmental models of GH deficiency (GHD) and excess indicate that GH is positively associated with β-cell mass. Therefore, the reduction in GH levels observed with age and weight gain may contribute to the age-related decline in β-cell function. To test this hypothesis, β-cell mass and function were assessed in a mouse model of adult-onset isola...

Obestatin is a 23 amino acid, amidated-peptide that is encoded by the ghrelin gene. Previous studies have shown obestatin can modulate the hypothalamic neuronal circuitry that regulates pituitary function, perhaps by modulating the actions of ghrelin. However, the direct actions of obestatin on pituitary function remain controversial. Here, primary...

l-arginine (l-Arg) rapidly stimulates GH and insulin release in vivo. It has been hypothesized that l-Arg stimulates GH release by lowering hypothalamic somatostatin (SST) tone. l-Arg may also act directly at the pituitary to stimulate GH release. Moreover, l-Arg has a direct stimulatory effect on β-cells, which is thought to be blunted by the rele...

Insulin-like growth factor I (IGF-I) is considered a primary inhibitor of GH secretion. Insulin may also play an important role in regulating GH levels since insulin, like IGF-I, can suppress GH synthesis and release in primary pituitary cell cultures and insulin is negatively correlated with GH levels in vivo. However, understanding the relative c...

Ghrelin-system components [native ghrelin, In1-ghrelin, Ghrelin-O-acyltransferase enzyme (GOAT) and receptors (GHS-Rs)] are expressed in a wide variety of tissues, including the pancreas, where they exert different biological actions including regulation of neuroendocrine secretions, food intake and pancreatic function. The expression of ghrelin sy...

Adiponectin is an adipokine that is positively correlated with longevity and negatively correlated with many obesity-related diseases. While there are several circulating forms of adiponectin, the high molecular weight (HMW) version has the predominate bioactivity. Adiponectin levels are of particular interest in mice with altered growth hormone (G...

In mice, GH levels rise in response to short-term fasting or starvation (food restriction to 40% of ad libitum intake), similar to that which occurs in humans in response to fasting or anorexia. Recent studies using acyl-ghrelin knockout mice have suggested that the rise in GH during food restriction is essential to support glucose levels. To direc...

It has been suggested that adult metabolic dysfunction may be more severe in individuals who become obese as children, compared to those who become obese later in life. To determine if adult metabolic function differs if diet-induced weight gain occurs during the peripubertal age versus if excess weight gain occurs after puberty, male C57Bl/6J mice...

The metabolic actions of the ghrelin gene-derived peptide obestatin are still unclear. We investigated obestatin effects in vitro, on adipocyte function, and in vivo, on insulin resistance and inflammation in mice fed a high-fat diet (HFD). Obestatin effects on apoptosis, differentiation, lipolysis, and glucose uptake were determined in vitro in mo...

Cortistatin (CST) and somatostatin (SST) evolve from a common ancestral gene and share remarkable structural, pharmacological, and functional homologies. Although CST has been considered as a natural SST-analogue acting through their shared receptors (SST receptors 1-5), emerging evidence indicates that these peptides might in fact exert unique rol...

A unique mouse model was developed with elevated endogenous GH (2- to 3-fold) and IGF-I (1.2- to 1.4-fold), due to somatotrope-specific Cre-mediated inactivation of IGF-I receptor (IgfIr) and insulin receptor (Insr) genes (IgfIr,Insr(rGHpCre), referred to as HiGH mice). We demonstrate that the metabolic phenotype of HiGH mice is diet dependent and...

Somatostatin and cortistatin have been shown to act directly on pituitary somatotrophs to inhibit growth hormone (GH) release. However, previous results from nonprimate species indicate that these peptides can also directly stimulate GH secretion, at low concentrations. The relevance of this phenomenon in a nonhuman primate model was investigated i...

Secretion of GH by pituitary somatotrophs is primarily stimulated by GHRH and ghrelin and inhibited by somatostatin through the activation of specific receptors [GHRH receptor (GHRH-R), GH secretagogue receptor (GHS-R) and somatostatin receptors (sst1-5), respectively]. However, we have shown that somatostatin, at low doses, can also stimulate GH r...

Alzheimer's disease (AD) is a multifactorial progressive neurodegenerative disorder characterized by loss of memory and cognitive deficits, strongly influenced by the metabolic status, in which the impairment of neuropeptides/neurotransmitters systems has been previously observed. Ghrelin is a multifunctional hormone produced in a wide variety of t...

Somatostatin receptors (sst1-5) are present in different types of tumors, where they inhibit key cellular processes such as proliferation and invasion. Although ssts are densely expressed in breast cancer, especially sst2, their role and therapeutic potential remain uncertain. Recently, we identified a new truncated sst5 variant, sst5TMD4, which is...

The human ghrelin gene, which encodes the ghrelin and obestatin peptides, contains 5 exons (Ex), with Ex1-Ex4 encoding a 117 amino-acid (aa) preproprotein that is known to be processed to yield a 28-aa (ghrelin) and/or a 23-aa (obestatin) mature peptides, which possess biological activities in multiple tissues. However, the ghrelin gene also encode...

Kisspeptins (Kps) have emerged as key players in the control of reproductive-axis function, in which they operate as primary regulators of hypothalamic GnRH release. In addition, recent data indicate that Kps can also directly act on the pituitary to stimulate LH and GH release in primary pituitary cell culture prepared from rats, cows, and sheep....

Somatostatin (SST) and cortistatin (CORT) act through a family of seven transmembrane domain (TMD) receptors (sst1-5) to govern multiple functions, from growth hormone (GH) secretion to neurotransmission, metabolic homeostasis, gastrointestinal and immune function, and tumor cell growth. Thus, SST analogs are used to treat endocrine/tumoral patholo...