Jesse Roth

TRP64ARG β3-adrenergic receptor and obesity in Mexican Americans

Abstract The β3-adrenergic receptor (β3AR) is expressed in visceral fat and is a regulator of resting metabolic rate, thermogenesis, and lipolysis. We genotyped 61 unrelated Mexican Americans for a variant in the β3AR gene (codon 64 TGGTrp→CGGArg; TRP64ARG). The allele frequency was 0.13. The TRP64ARG variant was significantly associated with an earlier age of onset of non-insulin-dependent diabetes mellitus (41.3 ± 4.6 years vs 55.6 ± 2.6 years; P < 0.02) and in non-diabetics, with elevated 2-h insulin levels during an oral glucose tolerance test (810 ± 120 pmol/l vs 384 ± 6 pmol/l; P < 0.005). Non-diabetic subjects with the variant allele tended to have higher body mass indices (BMI), waist-to-hip ratios, and diastolic blood pressures. The study group was expanded to include 421 related subjects from 31 families in the San Antonio Family Diabetes Study. Using a measured genotype analysis approach to estimate genotype-specific means for each trait, those who were homozygous for the TRP64ARG variant had significantly higher 2-h insulin levels (P = 0.036) and trends towards higher BMI compared to the other two genotypes. We detected no associations of these traits in the TRP64ARG heterozygotes in the larger group. We conclude that the TRP64ARG β3AR variant is a susceptibility gene for several features of the insulin resistance syndrome in Mexican Americans. Since its effects are modest, study design (e.g., subject selection, genetic background, and statistical analyses) may influence which traits are associated with this variant and whether or not the effect is detectable in heterozygotes.

A Synthetic Peptide Derived from a COOH-terminal Domain of the Insulin Receptor Specifically Enhances Insulin Receptor Signaling

The role of the insulin receptor COOH-terminal domain in the regulation of insulin signal transduction was explored with a variety of synthetic peptides. One of the peptides, termed peptide HC, whose structure corresponds to residues 1293-1307 of the insulin proreceptor sequence, enhanced insulin-stimulated autophosphorylation of the insulin receptor in cell-free systems and in semipermeabilized Chinese hamster ovary (CHO) cells that had been transfected with an expression plasmid encoding the human insulin receptor (CHO/HIRc) at concentrations where there was no detectable effect on basal autophosphorylation levels or on receptor dephosphorylation. A lipophilic analogue of peptide HC, stearyl peptide HC, added to intact CHO/HIRc cells enhanced significantly insulin-stimulated insulin receptor autophosphorylation while having no effect on ligand-stimulated receptor phosphorylation in CHO cells overexpressing either the IGF-1 receptor or epidermal growth factor receptor. Addition of stearyl peptide HC to CHO/HIRc cells resulted in a 2.4 ± 0.3-fold increase in the amount of insulin-stimulated phosphatidylinositol 3-kinase detected in anti-IRS-1 immunoprecipitates and a 2.1 ± 0.6-fold increase in the levels of tyrosine phosphorylation of mitogen-activated protein kinase in response to insulin. Finally, a derivative of peptide HC coupled to a biotin moiety was prepared and showed to bind with the β-subunit of the wild-type insulin receptor and a truncated receptor that lacks 43 amino acids from its carboxyl terminus. However, there was little binding, if any, of the peptide with the IGF-1 receptors or the epidermal growth factor receptors. Taken together, our data demonstrate that a pentadecapeptide related to the carboxyl terminus of the insulin receptor binds to the insulin receptor β-subunit and that this interaction may contribute to the increased receptors intrinsic activity and signal transduction.

Transgenic hyperinsulinemia: A mouse model of insulin resistance and glucose intolerance without obesity

Type II diabetes represents the most common form of diabetes in humans and is a major cause of morbidity and mortality.1In any individual patient, the primary metabolic abnormality initiating this disease process remains elusive, in spite of extensive study of the human condition and multiple animal models.2–5 Most of these models share several features with human type II diabetes, including glucose intolerance associated with hyperinsulinemia, insulin resistance, and obesity. We describe here transgenic mice that represent a novel model of early type II diabetes. They share many physiologic characteristics with other rodent models of type II diabetes, but they are not obese. They are not the result of a poorly defined mutation that may cause extensive abnormalities beyond those seen in glucose homeostasis, and they are not the result of surgical or pharmacologic manipulation. The metabolic abnormalities seen in these transgenics result from the introduction of multiple copies of the normal human insulin gene into their genome.

New melanocortin-like peptide of E. coli can suppress inflammation via the mammalian melanocortin-1 receptor (MC1R): possible endocrine-like function for microbes of the gut

E. coli releases a 33 amino acid peptide melanocortin-like peptide of E. coli (MECO-1) that is identical to the C-terminus of the E. coli elongation factor-G (EF-G) and has interesting similarities to two prominent mammalian melanocortin hormones, alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropin (ACTH). Note that MECO-1 lacks HFRW, the common pharmacophore of the known mammalian melanocortin peptides. MECO-1 and the two hormones were equally effective in severely blunting release of cytokines (HMGB1 and TNF) from macrophage-like cells in response to (i) endotoxin (lipopolysaccharide) or (ii) pro-inflammatory cytokine HMGB-1. The in vitro anti-inflammatoty effects of MECO-1 and of alpha-MSH were abrogated by (i) antibody against melanocortin-1 receptor (MC1R) and by (ii) agouti, an endogenous inverse agonist of MC1R. In vivo MECO-1 was even more potent than alpha-MSH in rescuing mice from death due to (i) lethal doses of LPS endotoxin or (ii) cecal ligation and puncture, models of sterile and infectious sepsis, respectively.Gut bacteria: Helping out with hormones?A molecule released by the common bacterium E. coli may act like a hormone on cells in the gut, with beneficial anti-inflammatory effects. The molecule is a short protein fragment known as a peptide. Its hormone-like activity on cultured mammalian cells was discovered by an international team of researchers led by Jesse Roth at the Feinstein Institute for Medical Research in Manhasset, USA. The peptide shares structural similarities with two known mammalian hormones and binds to an identified hormone receptor molecule. In some circumstances, it was shown to save mice from death by suppressing damaging inflammation. This discovery could broaden our understanding of the beneficial effects of gut bacteria. If applicable in humans it could reveal another link in our subtle relationship with bacteria, and may lead to uses in preventive and therapeutic medicine.