Weighing in on the role of brown adipose tissue for treatment of obesity.

Brown adipose tissue (BAT) activation is an emerging target for obesity treatments due to its thermogenic properties stemming from its ability to shuttle energy through uncoupling protein 1 (Ucp1). Recent rodent studies show how BAT and white adipose tissue (WAT) activity can be modulated to increase the expression of thermogenic proteins. Consequently, these alterations enable organisms to endure cold-temperatures and elevate energy expenditure, thereby promoting weight loss.

The interplay of glucose-dependent insulinotropic polypeptide in adipose tissue.

Adipose tissue was once known as a reservoir for energy storage but is now considered a crucial organ for hormone and energy flux with important effects on health and disease. Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted from the small intestinal K cells, responsible for augmenting insulin release, and has gained attention for its independent and amicable effects with glucagon-like peptide 1 (GLP-1), another incretin hormone secreted from the small intestinal L cells. The GIP receptor (GIPR) is found in whole adipose tissue, whereas the GLP-1 receptor (GLP-1R) is not, and some studies suggest that GIPR action lowers body weight and plays a role in lipolysis, glucose/lipid uptake/disposal, adipose tissue blood flow, lipid oxidation, and free-fatty acid (FFA) re-esterification, which may or may not be influenced by other hormones such as insulin.

Small intestinal CaSR-dependent and CaSR-independent protein sensing regulates feeding and glucose tolerance in rats.

Proteins activate small intestinal calcium sensing receptor (CaSR) and/or peptide transporter 1 (PepT1) to increase hormone secretion, but the effect of small intestinal protein sensing and the mechanistic potential of CaSR and/or PepT1 in feeding and glucose regulation remain inconclusive. Here we show that, in male rats, CaSR in the upper small intestine is required for casein infusion to increase glucose tolerance and GLP1 and GIP secretion, which was also dependent on PepT1 (ref. ).

Synergistic Combinations of Gut- and Pancreas-Hormone-Based Therapies: Advancements in Treatments for Metabolic Diseases.

Metabolic diseases, such as obesity, type 2 diabetes mellitus (T2DM), cardiovascular disease, and liver disease, have become increasingly prevalent around the world. As an alternative to bariatric surgery, glucagon-like peptide 1 (GLP-1) receptor agonists have been at the forefront of weight loss medication to combat these metabolic complications. Recently, there has been an exciting rapid emergence of new weight loss medications that combine GLP-1 receptor (GLP-1R) agonists with other gut- and pancreatic-derived hormones, such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) receptor agonists.

Association of circulating branched chain fatty acids with insulin sensitivity and beta cell function in the PROMISE cohort.

Branched chain fatty acids (BCFAs) are mainly saturated fatty acids with a methyl branch on the penultimate or antepenultimate carbon atom. While BCFAs are endogenously produced via the catabolism of branched chain amino acids, the primary exogenous source of BCFAs in the human body is via the diet, including dairy products. Recently, BCFAs have been identified as having a potentially protective role in the etiology of cardiometabolic disorders although current literature is limited.

Association of branched chain fatty acids with cardiometabolic disorders in humans: a systematic review.

Context: Despite advances in treatments for cardiometabolic disorders such as type 2 diabetes mellitus and obesity, the increasing frequency of these conditions is of major clinical and public health concern. Therefore, primary prevention including diet and lifestyle approaches continues to play a key role in risk reduction. Meta-analyses of prospective cohort studies have documented inverse associations of dairy consumption with the incidence of different cardiometabolic disorders.

Glucagon receptor signaling at white adipose tissue does not regulate lipolysis.

Although the physiological role of glucagon receptor signaling in the liver is well defined, the impact of glucagon receptor (Gcgr) signaling on white adipose tissue (WAT) continues to be debated. Although numerous studies propose that glucagon stimulates WAT lipolysis, we lack evidence that physiological concentrations of glucagon regulate WAT lipolysis. In turn, we performed studies in both wild-type and WAT knockout mice to determine if glucagon regulates lipolysis at WAT in the mouse.

GIPR Is Predominantly Localized to Nonadipocyte Cell Types Within White Adipose Tissue.

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) augments glucose-dependent insulin secretion through its receptor expressed on islet β-cells. GIP also acts on adipose tissue; yet paradoxically, both enhanced and reduced GIP receptor (GIPR) signaling reduce adipose tissue mass and attenuate weight gain in response to nutrient excess. Moreover, the precise cellular localization of GIPR expression within white adipose tissue (WAT) remains uncertain.

Genomic and Non-Genomic Actions of Glucocorticoids on Adipose Tissue Lipid Metabolism.

Glucocorticoids (GCs) are hormones that aid the body under stress by regulating glucose and free fatty acids. GCs maintain energy homeostasis in multiple tissues, including those in the liver and skeletal muscle, white adipose tissue (WAT), and brown adipose tissue (BAT). WAT stores energy as triglycerides, while BAT uses fatty acids for heat generation.

TCF7 is not essential for glucose homeostasis in mice.

Objective: Glucose-dependent insulinotropic polypeptide (GIP) and Glucagon-like peptide-1 (GLP-1) are incretin hormones that exert overlapping yet distinct actions on islet β-cells. We recently observed that GIP, but not GLP-1, upregulated islet expression of Transcription Factor 7 (TCF7), a gene expressed in immune cells and associated with the risk of developing type 1 diabetes. TCF7 has also been associated with glucose homeostasis control in the liver.

Hematopoietic cell- versus enterocyte-derived dipeptidyl peptidase-4 differentially regulates triglyceride excursion in mice.

Postprandial triglycerides (TGs) are elevated in people with type 2 diabetes (T2D). Glucose-lowering agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, also reduce postprandial TG excursion. Although the glucose-lowering mechanisms of DPP-4 have been extensively studied, how the reduction of DPP-4 activity improves lipid tolerance remains unclear.

Proglucagon-Derived Peptides, Glucose-Dependent Insulinotropic Polypeptide, and Dipeptidyl Peptidase-4-Mechanisms of Action in Adipose Tissue.

Proglucagon-derived peptides (PGDPs) and related gut hormones exemplified by glucose-dependent insulinotropic polypeptide (GIP) regulate energy disposal and storage through actions on metabolically sensitive organs, including adipose tissue. The actions of glucagon, glucagon-like peptide (GLP)-1, GLP-2, GIP, and their rate-limiting enzyme dipeptidyl peptidase-4, include direct and indirect regulation of islet hormone secretion, food intake, body weight, all contributing to control of white and brown adipose tissue activity. Moreover, agents mimicking actions of these peptides are in use for the therapy of metabolic disorders with disordered energy homeostasis such as diabetes, obesity, and intestinal failure.

Proteomics-Based Comparative Mapping of the Secretomes of Human Brown and White Adipocytes Reveals EPDR1 as a Novel Batokine.

Adipokines secreted from white adipose tissue play a role in metabolic crosstalk and homeostasis, whereas the brown adipose secretome is less explored. We performed high-sensitivity mass-spectrometry-based proteomics on the cell media of human adipocytes derived from the supraclavicular brown adipose and from the subcutaneous white adipose depots of adult humans. We identified 471 potentially secreted proteins covering interesting categories such as hormones, growth factors, extracellular matrix proteins, and proteins of the complement system, which were differentially regulated between brown and white adipocytes.

Physiological roles of the GIP receptor in murine brown adipose tissue.

Objective: Glucose-dependent insulinotropic polypeptide (GIP) is secreted from the gut in response to nutrient ingestion and promotes meal-dependent insulin secretion and lipid metabolism. Loss or attenuation of GIP receptor (GIPR) action leads to resistance to diet-induced obesity through incompletely understood mechanisms. The GIPR is expressed in white adipose tissue; however, its putative role in brown adipose tissue (BAT) has not been explored.

The brown adipose tissue glucagon receptor is functional but not essential for control of energy homeostasis in mice.

Objective: Administration of glucagon (GCG) or GCG-containing co-agonists reduces body weight and increases energy expenditure. These actions appear to be transduced by multiple direct and indirect GCG receptor (GCGR)-dependent mechanisms. Although the canonical GCGR is expressed in brown adipose tissue (BAT) the importance of BAT GCGR activity for the physiological control of body weight, or the response to GCG agonism, has not been defined.

Fibroblast activation protein is dispensable for control of glucose homeostasis and body weight in mice.

Objective: Fibroblast Activation Protein (FAP), an enzyme structurally related to dipeptidyl peptidase-4 (DPP-4), has garnered interest as a potential metabolic drug target due to its ability to cleave and inactivate FGF-21 as well as other peptide substrates. Here we investigated the metabolic importance of FAP for control of body weight and glucose homeostasis in regular chow-fed and high fat diet-fed mice.

Methods: FAP enzyme activity was transiently attenuated using a highly-specific inhibitor CPD60 and permanently ablated by genetic inactivation of the mouse Fap gene.

Circulating Levels of Soluble Dipeptidyl Peptidase-4 Are Dissociated from Inflammation and Induced by Enzymatic DPP4 Inhibition.

Dipeptidyl peptidase-4 (DPP-4) controls glucose homeostasis through enzymatic termination of incretin action. We report that plasma DPP-4 activity correlates with body weight and fat mass, but not glucose control, in mice. Genetic disruption of adipocyte Dpp4 expression reduced plasma DPP-4 activity in older mice but did not perturb incretin levels or glucose homeostasis.

β-Cell Inactivation of Unmasks Incretin Dependence of GPR119-Mediated Glucoregulation.

GPR119 was originally identified as an orphan β-cell receptor; however, subsequent studies demonstrated that GPR119 also regulates β-cell function indirectly through incretin hormone secretion. We assessed the importance of GPR119 for β-cell function in mice and in newly generated mice. mice displayed normal body weight and glucose tolerance on a regular chow (RC) diet.

Glucocorticoid antagonism limits adiposity rebound and glucose intolerance in young male rats following the cessation of daily exercise and caloric restriction.

Severe caloric restriction (CR), in a setting of regular physical exercise, may be a stress that sets the stage for adiposity rebound and insulin resistance when the food restriction and exercise stop. In this study, we examined the effect of mifepristone, a glucocorticoid (GC) receptor antagonist, on limiting adipose tissue mass gain and preserving whole body insulin sensitivity following the cessation of daily running and CR. We calorically restricted male Sprague-Dawley rats and provided access to voluntary running wheels for 3 wk followed by locking of the wheels and reintroduction to ad libitum feeding with or without mifepristone (80 mg·kg(-1)·day(-1)) for 1 wk.

FTO Obesity Variant Circuitry and Adipocyte Browning in Humans.

Background: Genomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive.

Methods: We examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity.

Voluntary exercise improves metabolic profile in high-fat fed glucocorticoid-treated rats.

Diabetes is rapidly induced in young male Sprague-Dawley rats following treatment with exogenous corticosterone (CORT) and a high-fat diet (HFD). Regular exercise alleviates insulin insensitivity and improves pancreatic β-cell function in insulin-resistant/diabetic rodents, but its effect in an animal model of elevated glucocorticoids is unknown. We examined the effect of voluntary exercise (EX) on diabetes development in CORT-HFD-treated male Sprague-Dawley rats (∼6 wk old).

Effects of selective and non-selective glucocorticoid receptor II antagonists on rapid-onset diabetes in young rats.

The blockade of glucocorticoid (GC) action through antagonism of the glucocorticoid receptor II (GRII) has been used to minimize the undesirable effects of chronically elevated GC levels. Mifepristone (RU486) is known to competitively block GRII action, but not exclusively, as it antagonizes the progesterone receptor. A number of new selective GRII antagonists have been developed, but limited testing has been completed in animal models of overt type 2 diabetes mellitus.

Exogenous glucocorticoids and a high-fat diet cause severe hyperglycemia and hyperinsulinemia and limit islet glucose responsiveness in young male Sprague-Dawley rats.

Corticosterone (CORT) and other glucocorticoids cause peripheral insulin resistance and compensatory increases in β-cell mass. A prolonged high-fat diet (HFD) induces insulin resistance and impairs β-cell insulin secretion. This study examined islet adaptive capacity in rats treated with CORT and a HFD.

Duration of rise in free fatty acids determines salicylate's effect on hepatic insulin sensitivity.

We have shown in rats that sodium salicylate (SS), which inhibits IkBa kinase B (IKKB), prevents hepatic and peripheral insulin resistance caused by short-term (7  h) i.v. administration of Intralipid and heparin (IH).