Branched-chain amino acids (BCAAs) are essential amino acids that are not synthesized in our body; thus, they need to be obtained from food. They have shown to provide many physiological and metabolic benefits such as stimulation of pancreatic insulin secretion, milk production, adipogenesis, and enhanced immune function, among others, mainly mediated by mammalian target of rapamycin (mTOR) signaling pathway. After identified as a reliable marker of obesity and type 2 diabetes in recent years, an increasing number of studies have surfaced implicating BCAAs in the pathophysiology of other diseases such as cancers, cardiovascular diseases, and even neurodegenerative disorders like Alzheimer's disease. Here we discuss the most recent progress and review studies highlighting both correlational and potentially causative role of BCAAs in the development of these disorders. Although we are just beginning to understand the intricate relationships between BCAAs and some of the most prevalent chronic diseases, current findings raise a possibility that they are linked by a similar putative mechanism.

Obesity prevalence is increasing at an unprecedented rate throughout the world, and is a strong risk factor for metabolic, cardiovascular, and neurological/neurodegenerative disorders. While low-grade systemic inflammation triggered primarily by adipose tissue dysfunction is closely linked to obesity, inflammation is also observed in the brain or the central nervous system (CNS). Considering that the hypothalamus, a classical homeostatic center, and other higher cortical areas (e.g. prefrontal cortex, dorsal striatum, hippocampus, etc.) also actively participate in regulating energy homeostasis by engaging in inhibitory control, reward calculation, and memory retrieval, understanding the role of CNS oxidative stress and inflammation in obesity and their underlying mechanisms would greatly help develop novel therapeutic interventions to correct obesity and related comorbidities. Here we review accumulating evidence for the association between ER stress and mitochondrial dysfunction, the main culprits responsible for oxidative stress and inflammation in various brain regions, and energy imbalance that leads to the development of obesity. Potential beneficial effects of natural antioxidant and anti-inflammatory compounds on CNS health and obesity are also discussed.

Adipose tissue expansion involves angiogenesis to remodel its capillary network. The enzymemethionine aminopeptidase 2(MetAP2) promotes angiogenesis.MetAP2 inhibitors suppress angiogenesis and have potential anti-obesity effect. However, impairment in adipose tissue expansion is also linked with impaired glycemic control.This study investigated the effect of BL6, a MetAP2 inhibitor, on adipogenesis and glucose disposal.To test effect on angiogenesis, Human Umbilical Vein Endothelial Cells(HUVECs) were treated with BL6 for 24h to determine tube formation. Further, to test effect on adipogenesis and glucose disposal,3T3-L1 pre-adipocytes were treated with BL6(0 µM, 20µM, 50 µM or 100µM) during differentiation. Differentiated cells were stained with Oil Red O for determining lipid accumulation, and glucose uptake assay. Protein levels and RNA expression for key genes involved in the adipogenic cascade were determined.BL6 treatment of HUVECs dose dependently blocked angiogenesis. During differentiation of pre-adipocytes, 50μM and 100µM BL6 significantly reduced lipid accumulation. Treatment with 100µM BL6 significantly decreased expression of adipogenic genes. Interestingly, BL6 treatment dose dependently increased glucose uptake by 3T3-L1 cells.MetAP2 inhibitor blocks angiogenesis, attenuates adipogenesis, yet increases cellular glucose uptake. Collectively this proof of concept study supports a possible role for MetAP2 inhibitor BL6, as a putative anti-obesity therapeutic agent.

IntroductionOlder age is associated with greater prevalence of hyperinsulinemia, type 2 diabetes, and fatty liver disease. These metabolic conditions and aging are bidirectionally linked to mitochondrial dysfunction and telomere attrition. Although effectively addressing these conditions is important for influencing the health and the lifespan, it is particularly challenging in older age. We reported that E4orf1, a protein derived from human adenovirus Ad36, reduces hyperinsulinemia, improves glucose clearance, and protects against hepatic steatosis in younger mice exposed to high fat diet (HFD). Here, we tested if E4orf1 will improve glycemic control, liver fat accumulation, mitochondrial integrity, and reduce telomere attrition in older mice.Research design and methodsWe used 9-month-old mice that inducibly expressed E4orf1 in adipose tissue and non-E4orf1 expressing control mice. Mice were maintained on a 60% (kcal) HFD for 20 weeks and glycemic control was determined by intraperitoneal glucose tolerance test at week 20. Following 20 weeks of HF-feeding, mice were sacrificed and liver tissues collected to determine the expression of aging genes using qRT-PCR based RT2 Profiler PCR array.ResultsCompared with the control mice, E4orf1 significantly improved glycemic control and reduced hepatic steatosis and fibrosis. Additionally, E4orf1 maintained markers of mitochondrial integrity and telomere attrition.ConclusionE4orf1 has the potential to improve glycemic control in older mice, and the improvement persists even after longer term exposure. E4orf1 expression also maintains mitochondrial integrity and telomere attrition, thus delaying age-associated diseases. This provides strong evidence for therapeutic utility of E4orf1 in improving age-associated metabolic and cellular changes that occur with aging in humans.

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Objectives Alzheimer's disease (AD) is an irreversible neurodegenerative disorder that is the third leading cause of mortality in the US. AD brain is mainly characterized by accumulated plaques and tangles and diminished neurotransmitters. AD is strongly associated with type 2 diabetes (T2D). Emerging studies suggest that branched-chain amino acids (BCAAs), the essential amino acids we need to obtain from food, are involved in the pathogenesis of insulin resistance and T2D. In support of this concept, BCAA degradation is impaired in obese and/or diabetic individuals, and BCAA supplementation leads to insulin resistance and perturbed glycemic control. It is currently unknown if similar defective BCAA metabolism exists in AD patients. Since BCAAs along with aromatic amino acids are critical for production and maintenance of brain neurotransmitters, here we tested if BCAA metabolism in liver – an organ with the highest BCAA degradation activity – is impaired in AD. Methods Eight month-old wildtype or AD transgenic mice were fed a standard chow diet until sacrifice. Serum BCAA levels were measured by BCAA assay, and proteins and genes related to BCAA metabolism in liver were determined by western blot and RT-qPCR, respectively. Serum BCAA profile of healthy or AD individuals were assessed by metabolomics analysis. Results The activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in BCAA degradation pathway, in liver was significantly suppressed in AD mice compared to wildtypes as evidenced by the protein expression and its phosphorylated, inactive, state. This is supported by increased hepatic BCKDH Kinase at both protein and gene levels in AD mice. Serum BCAAs and/or their metabolites were higher in both AD mice and humans compared to healthy controls, indicating impaired BCAA metabolism. Conclusions Our findings suggest that hepatic BCAA catabolism is impaired in AD mice. This may lead to high plasma BCAAs and their metabolites that can potentially contribute to the imbalance of brain neurotransmitters and development of AD or related dementia. A longitudinal assessment of BCAA metabolism will allow us to determine if they play a predictive, diagnostic, and/or causal role in the development of AD. Funding Sources NIH DK099463, Wylie Briscoe Fund, Texas Tech University.

Objectives Since cardiovascular disease (CVD) is considered to be one of the most expanding collections of health disorders in terms of severity and progression, the relationship of maternal and offspring health risk factors with CVD needs study. The objective of this review was to identify how developmental origin and maternal health are related to disease progression in both mothers and their offspring, apart from general risk factors such as lifestyle, eating behavior and genetic factors. Methods A computer based literature search through PubMed, Medline, Google Scholar and Google Search was carried out. The keywords for searching included maternal health, cardiovascular diseases, maternal and offspring cardiovascular health and developmental origin. Results Increasing evidence demonstrates that women with pregnancy-related complications, such as preeclampsia, preterm birth and maternal hypertension, are at risk for CVD in any phase of their life. Further, maternal malnutrition plays an influential role in the progression of CVD in the adulthood of their offspring. Also, in-utero exposure to high cholesterol or maternal hypercholesterolemia can demonstrate early lesion of atherosclerosis in children. Conclusions A clearer perception on how different domains of maternal health complications independently or synergistically lead to CVD or vice-versa, as well as their impact on offspring's wellbeing, is required. This will assist in developing new preventive techniques and therapeutic treatments for CVD. Funding Sources Texas Tech University.