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Derangements in triglyceride and cholesterol metabolism (dyslipidemia) are major risk factors for the development of cardiovascular diseases in obese and type-2 diabetic (T2D) patients. An emerging class of glucagon-like peptide-1 (GLP-1) analogues and next generation peptide dual-agonists such as GLP-1/glucagon or GLP-1/GIP could provide effective therapeutic options for T2D patients. In addition to their role in glucose and energy homeostasis, GLP-1, GIP and glucagon serve as regulators of lipid metabolism. This review summarizes the current knowledge in GLP-1, glucagon and GIP effects on lipid and lipoprotein metabolism and frames the emerging therapeutic benefits of GLP-1 analogs and GLP-1-based multiagonists as add-on treatment options for diabetes associated dyslipidemia.

During mammalian energy homeostasis, the glucagon receptor (Gcgr) plays a key role in regulating both glucose and lipid metabolisms. However, the mechanisms by which these distinct signaling arms are differentially regulated remain poorly understood. Using a Cy5-glucagon agonist, we show that the endosomal protein Vps37a uncouples glucose production from lipid usage downstream of Gcgr signaling by altering intracellular receptor localization. Hepatocyte-specific knockdown of Vps37a causes an accumulation of Gcgr in endosomes, resulting in overactivation of the cAMP/PKA/p-Creb signaling pathway to gluconeogenesis without affecting β-oxidation. Shifting the receptor back to the plasma membrane rescues the differential signaling and highlights the importance of the spatiotemporal localization of Gcgr for its metabolic effects. Importantly, since Vps37a knockdown in animals fed with a high-fat diet leads to hyperglycemia, although its overexpression reduces blood glucose levels, these data reveal a contribution of endosomal signaling to metabolic diseases that could be exploited for treatments of type 2 diabetes.

The Allan-Herndon Dudley Syndrome (AHDS) is a rare disease caused by the progressive loss of monocarboxylate transporter 8 (MCT8). In patients with AHDS, the absence of MCT8 impairs transport of thyroid hormones (TH) through the blood brain barrier, leading to a central state of TH deficiency. In mice, the AHDS is mimicked by simultaneous deletion of the TH transporters MCT8 and the solute carrier organic anion transporter family member 1c1 (OATP1C1). To support preclinical mouse studies, an analytical methodology was developed and successfully applied for quantifying selected thyroid hormones in mouse whole brain and in specific regions using liquid chromatography tandem mass-spectrometry (LC-MS/MS). An important requirement for the methodology was its high sensitivity since a very low concentration of THs was expected in MCT8/OATP1C1 double-knockout (dko) mouse brain. Seven THs were targeted: L-thyroxine (T4), 3,3´,5‐triiodo‐L‐thyronine-thyronine (T3), 3,3´,5´‐triiodo‐L‐thyronine-thyronine (rT3), 3,3´‐diiodo‐L‐thyronine (3,3´‐T2, T2), 3,5-diiodo-L-thyronine (rT2, 3,5-T2), 3-iodo-L-thyronine (T1), 3-iodothyronamine (T1AM). Isotope dilution liquid chromatography triple-quadrupole mass spectrometry methodology was applied for detection and quantification. The method was validated in wild-type animals for mouse whole brain and for five different brain regions (hypothalamus, hippocampus, prefrontal cortex, brainstem and cortex). Instrumental calibration curves ranged from 0.35 to 150 pg/µL with good linearity (r2 >0.996). The limit of quantification was from 0.08 to 0.6 pg/mg, with an intra- and inter-day precision of 4.2–14.02% and 0.4–17.9% respectively, and accuracies between 84.9% and 114.8% when the methodology was validated for the whole brain. In smaller, distinct brain regions, intra- and inter-day precision were 0.6–20.7% and 2.5–15.6% respectively, and accuracies were 80.2–128.6%. The new methodology was highly sensitive and allowed for the following quantification in wild-type mice: (i) for the first time, four distinct thyroid hormones (T4, T3, rT3 and 3,3´‐T2) in only approximately 100 mg of mouse brain were detected; (ii) the quantification of T4 and T3 for the first time in distinct mouse brain regions were reported. Further, application of our method to MCT8/OATP1C1 dko mice revealed the expected, relative lack of T3 and T4 uptake into the brain, and confirmed the utility of our analytical method to study TH transport across the blood brain barrier in a preclinical model of central TH deficiency.

Meta-inflammation of hypothalamic areas governing energy homeostasis has recently emerged as a process of potential pathophysiological relevance for the development of obesity and its metabolic sequelae. The current model suggests that diet-induced neuronal injury triggers microgliosis and astrocytosis, conditions which ultimately may induce functional impairment of hypothalamic circuits governing feeding behavior, systemic metabolism, and body weight. Epidemiological data indicate that low circulating HDL levels, besides conveying cardiovascular risk, also correlate strongly with obesity. We simulated that condition by using a genetic loss of function mouse model (apoA-I(−/−)) with markedly reduced HDL levels to investigate whether HDL may directly modulate hypothalamic inflammation. Astrogliosis was significantly enhanced in the hypothalami of apoA-I(−/−) compared with apoA-I(+/+) mice and was associated with compromised mitochondrial function. apoA-I(−/−) mice exhibited key components of metabolic disease, like increased fat mass, fasting glucose levels, hepatic triglyceride content, and hepatic glucose output compared with apoA-I(+/+) controls. Administration of reconstituted HDL (CSL-111) normalized hypothalamic inflammation and mitochondrial function markers in apoA-I(−/−) mice. Treatment of primary astrocytes with apoA-I resulted in enhanced mitochondrial activity, implying that circulating HDL levels are likely important for astrocyte function. HDL-based therapies may consequently avert reactive gliosis in hypothalamic astrocytes by improving mitochondrial bioenergetics and thereby offering potential treatment and prevention for obesity and metabolic disease.

Liver-expressed antimicrobial peptide 2 (LEAP-2), the endogenous noncompetitive allosteric antagonist of the growth hormone secretagogue receptor 1a (GHSR1a), was recently identified as a key endocrine factor regulating systemic energy metabolism. This antagonist impairs the ability of ghrelin to activate GHSR1a and diminishes ghrelin-induced Ca2+ release in vitro. The physiological relevance of the molecular LEAP-2-GHSR1a interaction was subsequently demonstrated in vivo. LEAP-2 is therefore a promising therapeutic target in the treatment of obesity and other metabolic diseases. Here, we discuss not only the current understanding of LEAP-2 in metabolic regulation, but also the potential of this peptide in the treatment of obesity and other diseases that involve dysregulation of the ghrelin system.

Objective Technological advances have brought a steady increase in the availability of various types of omics data, from genomics to metabolomics. Integrating these multi-omics data is a chance and challenge for systems biology; yet, tools to fully tap their potential remain scarce. Methods We present here a fully unsupervised and versatile correlation-based method – termed Correlation guided Network Integration (CoNI) – to integrate multi-omics data into a hypergraph structure that allows for the identification of effective modulators of metabolism. Our approach yields single transcripts of potential relevance that map to specific, densely connected, metabolic subgraphs or pathways. Results By applying our method on transcriptomics and metabolomics data from murine livers under standard Chow or high-fat diet, we identified eleven genes with potential regulatory effects on hepatic metabolism. Five candidates, including the hepatokine INHBE, were validated in human liver biopsies to correlate with diabetes-related traits such as overweight, hepatic fat content, and insulin resistance (HOMA-IR). Conclusion Our method's successful application to an independent omics dataset confirmed that the novel CoNI framework is a transferable, entirely data-driven, flexible, and versatile tool for multiple omics data integration and interpretation., Graphical abstract Image 1

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 metabolic regulation in mice. Methods To address this question we evaluated the pharmacology of TB in various mouse models including those deficient in FGF21, GLP1 and GIP signaling. We also studied the ability of FAP to process FGF21 in vitro and TB to block FAP enzymatic activity. Results TB administration to diet-induced obese (DIO) animals led to profound decreases in body weight, reduced food consumption and adiposity, increased energy expenditure, improved glucose tolerance and insulin sensitivity, and lowered cholesterol levels. Total and intact plasma FGF21 were observed to be elevated in TB-treated DIO mice but not lean animals where the metabolic impact of TB was significantly attenuated. Furthermore, and in stark contrast to naïve DIO mice, the administration of TB to obese FGF21 knockout animals demonstrated no appreciable effect on body weight or any other measures of metabolism. In support of these results we observed no enzymatic degradation of human FGF21 at either end of the protein when FAP was inhibited in vitro by TB. Conclusions We conclude that pharmacological inhibition of FAP enhances levels of FGF21 in obese mice to provide robust metabolic benefits not observed in lean animals, thus validating this enzyme as a novel drug target for the treatment of obesity and diabetes., Highlights • Pharmacological inhibition of FAP reduces weight, improves glucose and lipid metabolism in obese, but not lean mice. • FAP inhibitor Talabostat at higher doses lessens food intake, without any apparent adverse effects in short term studies. • Obese FGF21 deficient mice did not exhibit meaningful change in metabolic regulation when treated with Talabostat. • The mechanism of Talabostat in vivo action appears to center on an increase in total and active levels of plasma FGF21. • FAP inhibition alone, or in combination with DPP4 is proposed as a novel approach to treat metabolic diseases.

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 based on observations of diminished responses of GIP to lower blood glucose in select patients, as well as evidence from rodent knockout models implying that GIP promotes obesity. These findings have prompted the belief in some, that inhibiting GIP action might be beneficial for metabolic diseases. However, a growing body of new evidence - including data based on refined genetically modified models and improved pharmacological agents - suggests a paradigm shift on how the GIP system should be manipulated for metabolic benefits.

SummaryCanonical 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 expenditure. In mice, global deficiency of catalytic subunit Ppp3cb, and tissue-specific ablation of regulatory subunit Ppp3r1 from skeletal muscle, but not adipose tissue or liver, led to protection from high-fat-diet-induced obesity and comorbid sequelæ. Ser637 hyperphosphorylation of dynamin-related protein 1 (Drp1) in skeletal muscle of calcineurin-deficient mice was associated with mitochondrial elongation into power-cable-shaped filaments and increased mitochondrial respiration, but also with attenuated exercise performance. Our data suggest that calcineurin acts as highly conserved pivot for the adaptive metabolic responses to environmental changes such as high-fat, high-sugar diets or exercise.

Hypothalamic inflammation is a potentially important process in the pathogenesis of high-fat diet-induced metabolic disorders that has recently received significant attention. Microglia are macrophage-like cells of the central nervous system which are activated by pro-inflammatory signals causing local production of specific interleukins and cytokines, and these in turn may further promote systemic metabolic disease. Whether or how this microglial activation can be averted or reversed is unknown. Since running exercise improves systemic metabolic health and has been found to promote neuronal survival as well as the recovery of brain functions after injury, we hypothesized that regular treadmill running may blunt the effect of western diet on hypothalamic inflammation. Using low-density lipoprotein receptor deficient (ldlr-/-) mice to better reflect human lipid metabolism, we first confirmed that microglial activation in the hypothalamus is severely increased upon exposure to a high-fat, or "western", diet. Moderate, but regular, treadmill running exercise markedly decreased hypothalamic inflammation in these mice. Furthermore, the observed decline in microglial activation was associated with an improvement of glucose tolerance. Our findings support the hypothesis that hypothalamic inflammation can be reversed by exercise and suggest that interventions to avert or reverse neuronal damage may offer relevant potential in obesity treatment and prevention. (C) 2012 Elsevier Inc. All rights reserved

Studies in rodent models demonstrated that the central cannabinoid receptor (Cnr1) mediates the orexigenic effects of cannabinoids. To analyze whether genetic variation in the cannabinoid receptor gene (CNR1) is implicated in human obesity, we initially genotyped 8 single nucleotide polymorphisms (SNPs) located in the 5' region (rs9353527, rs754387, rs6454676), intron 2 (rs806379, rs1535255), exon 3 (rs2023239), intron 3 (rs806370) and the coding region (rs1049353) in up to 364 German obesity trios (extremely obese child or adolescent and both parents). The transmission disequilibrium test (TDT) was negative for these SNPs (p>0.05). However, there was a slight trend towards preferential transmission of the A-allele of rs1049353 (p=0.12). We therefore genotyped this SNP in 235 independent German obesity families (at least two obese sibs and both parents) and in parallel screened the CNR1 coding region for sequence variations in 120 German extremely obese children and adolescents who mainly contributed to the initial trend observed for rs1049353. The trend for preferential transmission of the A-allele could not be substantiated (pedigree disequilibrium test, PDT p=0.15; A-allele less frequently transmitted). In the mutation screen we detected two rare variations, one novel non-conservative mutation (c.1256C>A; A419E) and the known variant 1419+1G>C. In addition, we confirmed the presence of rs1049353. As these variants could not explain the initial TDT, we conclude that there is no evidence for an association of CNR1 alleles with obesity in our study groups.

Pro-opiomelanocortin deficiency is a rare cause of severe intractable obesity. Two patients have experienced dramatic weight loss in response to setmelanotide, a melanocortin-4 receptor activator. The drug has potential in broader populations, but caution is warranted as it may act at other melanocortin receptors.

The adipocyte-derived hormone leptin is an important regulator of systemic energy metabolism. Transported via the circulation to the brain in proportion to fat mass, leptin promotes its biological action through activation of the long form of the leptin receptor (LepRb). Accordingly, binding of leptin to the extracellular domain of LepRb promotes transphosphorylation of the LepRb-associated Janus kinase 2 (JAK2), which in turn phosphorylates other tyrosine residues (Tyr985, Tyr1077, Tyr1138) along the intracellular tail of LepRb in order to facilitate downstream signaling [1]. The protein tyrosine phosphatase 1B (PTP1B) is an important negative regulator of leptin action due to its ability to directly inhibit LepRb-Jak2 signaling (Figure 1). The relevance of PTP1B to regulate energy metabolism was first shown in mice with global PTP1B deletion [2] and was later confirmed in a series of other studies. These whole body PTP1B deficient mice show decreased body weight, food intake and adiposity, leading to resistance to diet-induced obesity (DIO) and improved leptin sensitivity and glucose metabolism when exposed to a high-fat diet (HFD) [2]. Of appreciable note, mice with specific deletion of PTP1B in muscle, liver or adipose tissue show no overt changes in body weight, adiposity or glucose tolerance [3–5]. However, deletion of PTP1B specifically in the central nervous system (CNS) [6], in LepRb-expressing cells [7] and POMC neurons [8,9] mimics the results observed in the global PTP1B deficient mice. These studies strongly support the relevance of central PTP1B signaling in regulating energy metabolism. It remains unclear, however, whether and to what extent the metabolic benefits arising from central PTP1B deficiency depend on PTP1B׳s action within the hypothalamus and whether the observed effects on metabolism are mediated via hypothalamic leptin receptor signaling. An elegant step in solving these questions has now been taken by the group of Kendra Bence from the University of Pennsylvania [10]. In the current issue of Molecular Metabolism, Tsou and colleagues used mice with hypothalamus-specific expression of Cre recombinase (Nkx2.1 cre) to specifically delete PTP1B in the hypothalamus. Compared to wildtype control mice, these hypothalamus-specific PTP1B deficient mice (Nkx2.1 PTP1B−/−) show decreased body weight, adiposity and food intake under chronic HFD exposure. These data corroborate previous reports about the relevance of central PTP1B signaling in the regulation of systems metabolism. Moreover, they show for the first time that the hypothalamus plays a key role in mediating PTP1B׳s action on metabolism and that hypothalamic selective PTP1B deletion mimics the phenotype of the whole body, whole brain, LepRb-expressing cell and POMC neuronal PTP1B knockout mice [6–9]. To further assess whether the metabolic benefits observed in the hypothalamus-specific PTP1B−/− mice depend on hypothalamic leptin receptor signaling, the authors generated mice with concomitant deletion of PTP1B and the leptin receptor in the hypothalamus (Nkx2.1 PTP1B−/−: LepRb−/−). Interestingly, when comparing these double mutant mice with hypothalamus-specific LepRb deficient mice, the metabolic benefits of PTP1B deletion vanished. No difference in body weight, food intake, adiposity or glucose tolerance was observed when double mutant mice were compared to mice that lack only the leptin receptor, but not PTP1B, in the hypothalamus. Together, the data indicate that the improved body weight and adiposity that is observed upon hypothalamic PTP1B deletion is mediated via interaction of PTP1B and the leptin receptor in the hypothalamus and that the metabolic benefits arising from PTP1B deficiency thus depend on a functional leptin receptor in the hypothalamus. These results underscore the importance of hypothalamic leptin receptor signaling for the regulation of energy and glucose metabolism and highlight the role of PTP1B in systems metabolism. In summary, the recent data by Tsou et al., combined with a series of previous studies, make PTP1B an interesting target for studies aiming to improve leptin sensitivity in states of pathologically increased body weight. Figure 1 Schematic of how PTP1B affects intracellular leptin receptor signaling. Binding of leptin to the extracellular domain of LepRb leads to autophosphorylation of the Janus kinase 2 (JAK2). JAK2 in turn phosphorylates three LepRb tyrosine residues (Tyr985 ...