We describe a hypothalamus-specific mRNA that encodes preprohypocretin, the putative precursor of a pair of peptides that share substantial amino acid identities with the gut hormone secretin. The hypocretin (Hcrt) protein products are restricted to neuronal cell bodies of the dorsal and lateral hypothalamic areas. The fibers of these neurons are widespread throughout the posterior hypothalamus and project to multiple targets in other areas, including brainstem and thalamus. Hcrt immunoreactivity is associated with large granular vesicles at synapses. One of the Hcrt peptides was excitatory when applied to cultured, synaptically coupled hypothalamic neurons, but not hippocampal neurons. These observations suggest that the hypocretins function within the CNS as neurotransmitters.

/pdf/the-hypocretins-hypothalamus-specific-peptides-with-4pipr77drn.pdf

The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity

Biology of Incretins: GLP-1 and GIP

Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in ...

The Physiology of Glucagon-like Peptide 1

THE sequence of glucagon-like peptide-1 (7–36) amide (GLP-1) is completely conserved in all mammalian species studied, implying that it plays a critical physiological role1. We have shown that GLP-1 and its specific receptors are present in the hypo-thalamus2,3. No physiological role for central GLP-1 has been established. We report here that intracerebroventricular (ICV) GLP-1 powerfully inhibits feeding in fasted rats. ICV injection of the specific GLP-1-receptor antagonist, exendin (9-39)4, blocked the inhibitory effect of GLP-1 on food intake. Exendin (9-39) alone had no influence on fast-induced feeding but more than doubled food intake in satiated rats, and augmented the feeding response to the appetite stimulant, neuropeptide Y. Induction of c-fos is a marker of neuronal activation5. Following ICV GLP-1 injection, c-fos appeared exclusively in the paraventricular nucleus of the hypothalamus and central nucleus of the amygdala, and this was inhibited by prior administration of exendin (9-39). Both of these regions of the brain are of primary importance in the regulation of feeding6. These findings suggest that central GLP-1 is a new physiological mediator of satiety.

A role for glucagon-like peptide-1 in the central regulation of feeding

The "fetal" or "early" origins of adult disease hypothesis was originally put forward by David Barker and colleagues and stated that environmental factors, particularly nutrition, act in early life to program the risks for adverse health outcomes in adult life. This hypothesis has been supported by a worldwide series of epidemiological studies that have provided evidence for the association between the perturbation of the early nutritional environment and the major risk factors (hypertension, insulin resistance, and obesity) for cardiovascular disease, diabetes, and the metabolic syndrome in adult life. It is also clear from experimental studies that a range of molecular, cellular, metabolic, neuroendocrine, and physiological adaptations to changes in the early nutritional environment result in a permanent alteration of the developmental pattern of cellular proliferation and differentiation in key tissue and organ systems that result in pathological consequences in adult life. This review focuses on those experimental studies that have investigated the critical windows during which perturbations of the intrauterine environment have major effects, the nature of the epigenetic, structural, and functional adaptive responses which result in a permanent programming of cardiovascular and metabolic function, and the role of the interaction between the pre- and postnatal environment in determining final health outcomes.

https://www.physiology.org/doi/pdf/10.1152/physrev.00053.2003

Developmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming

Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells.

I. Introduction THE presence of intestinal factors regulating the function of endocrine secretion from the pancreas was first described in 1906 by Moore and colleagues (1). The idea that humoral factors secreted from the gut might act in this way arose after the recognition of “secretin” as a regulator of pancreatic secretion. Later it became evident that the hypoglycemic intestinal factor(s) is/are not “secretin” and the names “incretin” and “duodenin” were introduced in the 1920s and 1930s to describe these putative mediators (2–4). For several decades the nature of this/these factor(s) remained largely unknown (5–8) and before the first incretin hormone was chemically characterized, several other hormones produced in the gastrointestinal tract were discovered. The connection between the gastrointestinal tract and the endocrine pancreas was shown in the 1960s when insulin became measurable in plasma. In these classic studies, the insulin response to oral glucose and intravenous glucose, resulting in nea...

Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide

Background

Human gastroenteropancreatic neuroendocrine tumours are functionally and biologically heterogeneous, but their exact growth factor receptor expression pattern, important for onco- and carcinogenesis, remains unknown.



Methods

This study searched for the mRNA expression pattern of six tyrosine- and serine/threonine kinase receptors [hepatocyte growth factor (HGFR), fibroblast growth factor (FGFR), epidermal growth factor (EGFR), insulin-like growth factor (IGF)-1R, transforming growth factor (TGF)-βR1, TGF-βR2] together with the five somatostatin receptors in human gastroenteropancreatic neuroendocrine tumours (gastrinomas, insulinomas, tumours with carcinoid syndrome, functionally inactive neuroendocrine tumours) using reverse transcriptase-polymerase chain reaction (RT-PCR).



Results

EGF receptor was expressed almost exclusively in gastrinomas. Among the four tumour subtypes, expression frequencies of the somatostatin receptors 1 and 5, HGF-, IGF-1-, TGF-βR1, TGF-βR2 and the EGF-receptor varied significantly.



Conclusions

In spite of the common cellular origin of these tumours, differences in growth factor receptor expression suggest the existence of different pathways during tumour subtype development.

Growth factor receptor expression in human gastroenteropancreatic neuroendocrine tumours

Leptin: A Potent Inhibitor of Insulin Secretion

Cloning and sequence analysis of cDNAs and DNA fragments from genomic libraries has led to a dramatic increase in understanding of the glucagon-related peptides in recent years. The primary structure of the biosynthetic precursor of glucagon (preproglucagon) has been elucidated. The complex structural connec- tions between the multiple molecular forms of the glucagon-like peptides in tissues and in the circulation have been determined [ 1,2]. Mammalian proglucagon consists of 160 amino acid residues and is synthesized in the islets of Langerhans, intestine and brain. An exciting recent finding is that in addition to glucagon the preproglucagon gene in mammals encodes two additional peptides with struc- tural similarity to glucagon, termed glucagon-like peptide-1 and -2 (GLP-I and GLP-2). The truncated form of GLP-1, GLP-1(7-36) amide, which is secreted by the mammalian intestine, strongly stimulates insu- lin secretion and inhibits gastric acid secretion. This review focuses mainly on the truncated form of GLP-1. since a rapidly increasing number of reports indicate a remarkable interest of investigators in this particular hormone, which actually fulfills the classical role of an ‘enterogastrone’ and ‘incretin’ hormone. The purpose here is to describe what is known so far about the origin, processing, organ distribution and actions of this peptide and to search for promising future direc- tions of further investigations.

Hans-Christoph Fehmann

Papers

Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells.

Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide

Growth factor receptor expression in human gastroenteropancreatic neuroendocrine tumours

Leptin: A Potent Inhibitor of Insulin Secretion

Glucagon-like peptide-1(7-36) amide is a new incretin/enterogastrone candidate.