Global energy balance in mammals is controlled by the actions of circulating hormones that coordinate fuel production and utilization in metabolically active tissues. Bone-derived osteocalcin, in its undercarboxylated, hormonal form, regulates fat deposition and is a potent insulin secretagogue. Here, we show that insulin receptor (IR) signaling in osteoblasts controls osteoblast development and osteocalcin expression by suppressing the Runx2 inhibitor Twist2. Mice lacking IR in osteoblasts have low circulating undercarboxylated osteocalcin and reduced bone acquisition due to decreased bone formation and deficient numbers of osteoblasts. With age, these mice develop marked peripheral adiposity and hyperglycemia accompanied by severe glucose intolerance and insulin resistance. The metabolic abnormalities in these mice are improved by infusion of exogenous undercarboxylated osteocalcin. These results indicate the existence of a bone-pancreas endocrine loop through which insulin signaling in the osteoblast ensures osteoblast differentiation and stimulates osteocalcin production, which in turn regulates insulin sensitivity and pancreatic insulin secretion to control glucose homeostasis.

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SUMMARY Insulin resistance and elevated glucagon levels result in non-suppressible hepatic glucose production and hyperglycemia in patients with type 2 diabetes. The CREB co-activator complex controls transcription of hepatic gluconeogenic enzyme genes. Here we show that both the antidiabetic agent metformin and insulin phosphorylate the transcriptional co-activator CBP at serine 436 via PKCι/λ. This event triggers the dissociation of the CREB-CBP-TORC2 transcription complex and reduces gluconeogenic enzyme gene expression. Mice carrying a germline mutation of this CBP phosphorylation site (S436A) demonstrate resistance to the hypoglycemic effect of both insulin and metformin. Obese, hyperglycemic mice display hepatic insulin resistance, but metformin is still effective in treating the hyperglycemia of these mice since it stimulates CBP phosphorylation by bypassing the block in insulin signaling.

T ranscription factors are critical in early pancreatic development, cell lineage specification, and the expression of differentiation-specific genes (1). At least 5 distinct gene loci encoding pancreatic transcription factors have been identified that, when mutated, lead to both early-and late-onset forms of type 2 diabetes (2,3). One of these loci encodes the homeodomain transcription factor IDX-1 (also known as PDX-1, IPF-1, and STF-1). IDX-1 is required for early pancreas development, and it regulates glucose-responsive insulin gene transcription and the transcription of the ␤-cell genes GLUT2, glucokinase, and islet amyloid polypeptide (3-5). The homozygous idx-1 null mouse (6) and a child homozygous for an inactivating mutation in the idx-1 gene (7) fail to develop a pancreas (pancreatic agenesis). The heterozygous idx-1 (+/-) mouse develops a pancreas but becomes glucose intolerant during adulthood as a result of smaller islets and decreased numbers of ␤-cells (8). Furthermore, idx-1 (ipf-1) haploinsufficient family members of a child born with pancreatic agenesis who carry one inactive idx-1 allele manifest earlyonset diabetes, maturity-onset diabetes of the young type 4

Ghrelin is a gastric peptide hormone that stimulates weight gain in vertebrates. The biological activities of ghrelin require octanoylation of the peptide on Ser3, an unusual post-translational modification that is catalyzed by the enzyme ghrelin O-acyltransferase (GOAT). Here, we describe the design, synthesis, and characterization of GO-CoA-Tat, a peptide-based bisubstrate analog that antagonizes GOAT. GO-CoA-Tat potently inhibits GOAT in vitro, in cultured cells, and in mice. Intraperitoneal administration of GO-CoA-Tat improves glucose tolerance and reduces weight gain in wild-type mice but not in ghrelin-deficient mice, supporting the concept that its beneficial metabolic effects are due specifically to GOAT inhibition. In addition to serving as a research tool for mapping ghrelin actions, GO-CoA-Tat may help pave the way for clinical targeting of GOAT in metabolic diseases.The persistent rise in the proportion of overweight individuals in Western society over the past 30 years has been associated with substantial excess morbidity and is widely recognized as a major public health concern. To address this problem, intensive efforts are underway to ‡ To whom correspondence should be addressed. pcole@jhmi.edu. * These authors contributed equally to this work. † These authors contributed equally to this work. clarify nutrient-hormone interactions contributing to weight gain. Starting with the isolation of leptin (1), a series of hormones acting centrally and peripherally to influence body mass have been discovered. Among these, the gastric peptide hormone acyl ghrelin has generated considerable interest as an important stimulus for weight gain (2-5) and modulator of glucose homeostasis (6-8). Various strategies in therapeutic development have been devised to antagonize acyl ghrelin (9,10), although none has yet emerged as clinically beneficial. Acyl ghrelin has an unusual Ser3 octanoylation; only acylated ghrelin can bind and activate the growth hormone secretagogue receptor (GHSR-1a). The cDNA for the enzyme responsible for this esterification, GOAT, has recently been cloned (11,12). GOAT has been suggested as a potential therapeutic target for modulating weight gain and glucose control, but thishas not yet been directly tested (9,13). An acyl ghrelin product analog Dap-ghrelin blocks GOAT activity in a microsomal assay (14).We designed bisubstrate analog GO-CoA-Tat based on the theory that if GOAT uses a ternary complex mechanism which templates octanoyl-CoA and ghrelin peptide, then linking the two substrates with a non-cleavable bridge could combine the binding energies of the individual ligands without the entropic loss associated with forming the ternary complex (Fig. 1A). A related strategy has been used for other peptide modifying enzymes including histone acetyltransferases (HAT) and protein kinases (15,16). Since we were uncertain about the ghrelin peptide length needed for recognition by GOAT, we selected amino acids 1-10 for coupling to octanoyl-CoA, to maximize inclusion of highly conserved...

Summary Early in the pathogenesis of Type 2 diabetes mellitus (T2DM), dysregulated glucagon secretion from pancreatic α-cells occurs prior to impaired glucose stimulated insulin secretion (GSIS) from β-cells. However, whether hyperglucagonemia is causally linked to β-cell dysfunction remains unclear. Here we show that glucagon stimulates via cAMP-PKA-CREB signaling hepatic production of the neuropeptide kisspeptin1, which acts on β-cells to suppress GSIS. Synthetic kisspeptin suppresses GSIS in vivo in mice and from isolated islets in a kisspeptin1 receptor-dependent manner. Kisspeptin1 is increased in livers and in serum from humans with T2DM and from mouse models of diabetes mellitus. Importantly, liver Kiss1 knockdown in hyperglucagonemic, glucose intolerant high fat diet fed and Leprdb/db mice augments GSIS and improves glucose tolerance. These observations indicate a hormonal circuit between the liver and the endocrine pancreas in glycemia regulation and suggest in T2DM a sequential link between hyperglucagonemia via hepatic kisspeptin1 to impaired insulin secretion.

SUMMARY Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients’ hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood. We show here that pharmacological metformin concentration increases mitochondrial respiration, membrane potential, and ATP levels in hepatocytes and a clinically relevant metformin dose increases liver mitochondrial density and complex 1 activity along with improved hyperglycemia in high-fat- diet (HFD)-fed mice. Metformin, functioning through 5′ AMP-activated protein kinase (AMPK), promotes mitochondrial fission to improve mitochondrial respiration and restore the mitochondrial life cycle. Furthermore, HFD-fed-mice with liver-specific knockout of AMPKα1/2 subunits exhibit higher blood glucose levels when treated with metformin. Our results demonstrate that activation of AMPK by metformin improves mitochondrial respiration and hyperglycemia in obesity. We also found that supra-pharmacological metformin concentrations reduce adenine nucleotides, resulting in the halt of mitochondrial respiration. These findings suggest a mechanism for metformin’s anti-tumor effects.

Sclerostin has traditionally been thought of as a local inhibitor of bone acquisition that antagonizes the profound osteoanabolic capacity of activated Wnt/β-catenin signaling, but serum sclerostin levels in humans exhibit a correlation with impairments in several metabolic parameters. These data, together with the increased production of sclerostin in mouse models of type 2 diabetes, suggest an endocrine function. To determine whether sclerostin contributes to the coordination of whole-body metabolism, we examined body composition, glucose homeostasis, and fatty acid metabolism in Sost mice as well as mice that overproduce sclerostin as a result of adeno-associated virus expression from the liver. Here, we show that in addition to dramatic increases in bone volume, Sost mice exhibit a reduction in adipose tissue accumulation in association with increased insulin sensitivity. Sclerostin overproduction results in the opposite metabolic phenotype due to adipocyte hypertrophy. Additionally, Sost mice and those administered a sclerostin-neutralizing antibody are resistant to obesogenic diet-induced disturbances in metabolism. This effect appears to be the result of sclerostin's effects on Wnt signaling and metabolism in white adipose tissue. Since adipocytes do not produce sclerostin, these findings suggest an unexplored endocrine function for sclerostin that facilitates communication between the skeleton and adipose tissue.