energy storage, membrane components, and signaling. Extracellular hydrolysis of dietary TG in circulating lipoproteins yields FFAs and sn -2 MG, which are then taken up by cells ( 1,2 ). MGs are also produced intracellularly from membrane phospholipids and the consecutive action of phospholipase C and diacylglycerol lipase, or from the hydrolysis of stored TG by adipose TG lipase (ATGL) and hormone sensitive lipase (HSL) ( 2-5 ). The ultimate fate of intracellular MGs is hydrolysis to FFAs and glycerol or reesterifi cation by acyltransferases into diacylglycerol and TG ( 6, 7 ).MG lipase (MGL) is considered the rate-determining enzyme in MG catabolism. MGL accounts for roughly 85% of MG hydrolysis in the brain, with the remainder being catalyzed by the enzymes ABHD6 and ABHD12 ( 8,9 ). MGL is expressed in many other tissues as well, including brain, liver, skeletal muscle, adipose, and intestine ( 10-13 ). Within cells, MGL localizes to both the cytosolic and membrane fractions and hydrolyzes sn -1 and sn -2 MGs of varying acyl chain lengths and degrees of unsaturation, with almost no activity toward other lipids, such as TG and lyso-phospholipids ( 10,(14)(15)(16)(17)(18).MGL is involved in energy balance through two important functions. Abbreviations: AA, arachidonic acid; AEA, arachidonoyl ethanolamide; 2-AG, 2-arachidonoyl glycerol; AUC, area under the curve; CB, cannabinoid; EC, endocannabinoid; HFD, high-fat diet; HOMA-IR, homeostatic model assessment of insulin resistance; iMGL, mice that overexpress monoacylglycerol lipase specifi cally in the intestinal mucosa; LFD, low-fat diet; MG, monoacylglycerol; MGL, monoacylglycerol lipase; OFTT, oral fat tolerance test; OGTT, oral glucose tolerance test; RER, respiratory exchange ratio .

Expressed in the small intestine, retinol-binding protein 2 (RBP2) facilitates dietary retinoid absorption. Rbp2-deficient (Rbp2−/−) mice fed a chow diet exhibit by 6-7 months-of-age higher body weights, impaired glucose metabolism, and greater hepatic triglyceride levels compared to controls. These phenotypes are also observed when young Rbp2−/− mice are fed a high fat diet. Retinoids do not account for the phenotypes. Rather, RBP2 is a previously unidentified monoacylglycerol (MAG)-binding protein, interacting with the endocannabinoid 2-arachidonoylglycerol (2-AG) and other MAGs with affinities comparable to retinol. X-ray crystallographic studies show that MAGs bind in the retinol binding pocket. When challenged with an oil gavage, Rbp2−/− mice show elevated mucosal levels of 2-MAGs. This is accompanied by significantly elevated blood levels of the gut hormone GIP (glucose-dependent insulinotropic polypeptide). Thus, RBP2, in addition to facilitating dietary retinoid absorption, modulates MAG metabolism and likely signaling, playing a heretofore unknown role in systemic energy balance.

Intestinal-fatty acid binding protein (IFABP; FABP2) is a 15-kDa intracellular protein abundantly present in the cytosol of the small intestinal (SI) enterocyte. High-fat (HF) feeding of IFABP−/− mice resulted in reduced weight gain and fat mass relative to wild-type (WT) mice. Here, we examined intestinal properties that may underlie the observed lean phenotype of high fat-fed IFABP−/− mice. No alterations in fecal lipid content were found, suggesting that the IFABP−/− mice are not malabsorbing dietary fat. However, the total excreted fecal mass, normalized to food intake, was increased for the IFABP−/− mice relative to WT mice. Moreover, intestinal transit time was more rapid in the IFABP−/− mice. IFABP−/− mice displayed a shortened average villus length, a thinner muscularis layer, reduced goblet cell density, and reduced Paneth cell abundance. The number of proliferating cells in the crypts of IFABP−/− mice did not differ from that of WT mice, suggesting that the blunt villi phenotype is not due to alterations in proliferation. IFABP−/− mice were observed to have altered expression of genes and proteins related to intestinal structure, while immunohistochemical analyses revealed increased staining for markers of inflammation. Taken together, these studies indicate that the ablation of IFABP, coupled with high-fat feeding, leads to changes in gut motility and morphology, which likely contribute to the relatively leaner phenotype occurring at the whole-body level. Thus, IFABP is likely involved in dietary lipid sensing and signaling, influencing intestinal motility, intestinal structure, and nutrient absorption, thereby impacting systemic energy metabolism. NEW & NOTEWORTHY Intestinal fatty acid binding protein (IFABP) is thought to be essential for the efficient uptake and trafficking of dietary fatty acids. In this study, we demonstrate that high-fat-fed IFABP−/− mice have an increased fecal output and are likely malabsorbing other nutrients in addition to lipid. Furthermore, we observe that the ablation of IFABP leads to marked alterations in intestinal morphology and secretory cell abundance.

Heart disease is widely recognized as a major cause of death worldwide and is the leading cause of mortality in the United States. Centuries of research have focused on defining mechanistic alterations that drive cardiac pathogenesis, yet sudden cardiac death (SCD) remains a common unpredictable event that claims lives in every age group. The heart supplies blood to all tissues while maintaining a constant electrical and hormonal feedback communication with other parts of the body. As such, recent research has focused on understanding how myocardial electrical and structural properties are altered by cardiac metabolism and the various signaling pathways associated with it. The importance of cardiac metabolism in maintaining myocardial function, or lack thereof, is exemplified by shifts in cardiac substrate preference during normal development and various pathological conditions. For instance, a shift from fatty acid (FA) oxidation to oxygen-sparing glycolytic energy production has been reported in many types of cardiac pathologies. Compounded by an uncoupling of glycolysis and glucose oxidation this leads to accumulation of undesirable levels of intermediate metabolites. The resulting accumulation of intermediary metabolites impacts cardiac mitochondrial function and dysregulates metabolic pathways through several mechanisms, which will be reviewed here. Importantly, reversal of metabolic maladaptation has been shown to elicit positive therapeutic effects, limiting cardiac remodeling and at least partially restoring contractile efficiency. Therein, the underlying metabolic adaptations in an array of pathological conditions as well as recently discovered downstream effects of various substrate utilization provide guidance for future therapeutic targeting. Here, we will review recent data on alterations in substrate utilization in the healthy and diseased heart, metabolic pathways governing cardiac pathogenesis, mitochondrial function in the diseased myocardium, and potential metabolism-based therapeutic interventions in disease.

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Diabetes is a metabolic syndrome rooted in impaired insulin and/or glucagon secretory responses within the pancreatic islets of Langerhans (islets). Insulin secretion is primarily regulated by two key factors: glucose-mediated ATP production and G-protein coupled receptors (GPCRs) signaling. GPCR kinase 2 (GRK2), a key regulator of GPCRs, is reported to be downregulated in the pancreas of spontaneously obesogenic and diabetogenic mice (ob/ob). Moreover, recent studies have shown that GRK2 non-canonically localizes to the cardiac mitochondrion, where it can contribute to glucose metabolism. Thus, islet GRK2 may impact insulin secretion through either mechanism. Utilizing Min6 cells, a pancreatic ß-cell model, we knocked down GRK2 and measured glucose-mediated intracellular calcium responses and insulin secretion. Silencing of GRK2 attenuated calcium responses, which were rescued by pertussis toxin pre-treatment, suggesting a Gαi/o-dependent mechanism. Pancreatic deletion of GRK2 in mice resulted in glucose intolerance with diminished insulin secretion. These differences were due to diminished insulin release rather than decreased insulin content or gross differences in islet architecture. Furthermore, a high fat diet feeding regimen exacerbated the metabolic phenotype in this model. These results suggest a new role for pancreatic islet GRK2 in glucose-mediated insulin responses that is relevant to type 2 diabetes disease progression.

Research efforts in the twenty-first century have been paramount to the discovery and development of novel pharmacological treatments in a variety of diseases resulting in improved life expectancy. Yet, cardiac disease remains a leading cause of morbidity and mortality worldwide. Over time, there has been an expansion in conditions such as atrial fibrillation (AF) and heart failure (HF). Although past research has elucidated specific pathways that participate in the development of distinct cardiac pathologies, the exact mechanisms of action leading to disease remain to be fully characterized. Protein turnover and cellular bioenergetics are integral components of cardiac diseases, highlighting the importance of mitochondria and endoplasmic reticulum (ER) in driving cellular homeostasis. More specifically, the interactions between mitochondria and ER are crucial to calcium signaling, apoptosis induction, autophagy, and lipid biosynthesis. Here, we summarize mitochondrial and ER functions and physical interactions in healthy physiological states. We then transition to perturbations that occur in response to pathophysiological challenges and how this alters mitochondrial–ER and other intracellular organelle interactions. Finally, we discuss lifestyle interventions and innovative therapeutic targets that may be used to restore beneficial mitochondrial and ER interactions, thereby improving cardiac function.

Intestinal fatty acid-binding protein (IFABP; FABP2) and liver fatty acid-binding protein (LFABP; FABP1) are small intracellular lipid-binding proteins. Deficiency of either of these proteins in mice leads to differential changes in intestinal lipid transport and metabolism, and to markedly divergent changes in whole-body energy homeostasis. The gut microbiota has been reported to play a pivotal role in metabolic process in the host and can be affected by host genetic factors. Here, we examined the phenotypes of wild-type (WT), LFABP−/−, and IFABP−/− mice before and after high-fat diet (HFD) feeding and applied 16S rRNA gene V4 sequencing to explore guild-level changes in the gut microbiota and their associations with the phenotypes. The results show that, compared with WT and IFABP−/− mice, LFABP−/− mice gained more weight, had longer intestinal transit time, less fecal output, and more guilds containing bacteria associated with obesity, such as members in family Desulfovibrionaceae. By contrast, IFABP−/− mice gained the least weight, had the shortest intestinal transit time, the most fecal output, and the highest abundance of potentially beneficial guilds such as those including members from Akkermansia, Lactobacillus, and Bifidobacterium. Twelve out of the eighteen genotype-related bacterial guilds were associated with body weight. Interestingly, compared with WT mice, the levels of short-chain fatty acids in feces were significantly higher in LFABP−/− and IFABP−/− mice under both diets. Collectively, these studies show that the ablation of LFABP or IFABP induced marked changes in the gut microbiota, and these were associated with HFD-induced phenotypic changes in these mice.