Betatrophin:A liver-derived hormone for the pancreatic β-cell proliferation

The pancreaticβ-cell failure which invariably accompanies insulin resistance in the liver and skeletal muscle is a hallmark of type-2 diabetes mellitus(T2DM).The persistent hyperglycemia of T2DM is often treated with anti-diabetic drugs with or without subcutaneous insulin injections,neither of which mimic the physiological glycemic control seen in individuals with fully functional pancreas.A sought after goal for the treatment of T2DM has been to harness the regenerative potential of pancreaticβ-cells that might obviate a need for exogenous insulin injections.A new study towards attaining this aim was reported by Yi et al,who have characterized a liver-derived protein,named betatrophin,capable of inducing pancreaticβ-cell proliferation in mice.Using a variety of in vitro and in vivo methods,Yi et al,have shown that betatrophin was expressed mainly in the liver and adipose tissue of mice.Exogenous expression of betatrophin in the liver led to dramatic increase in the pancreaticβ-cell mass and higher output of insulin in mice that also concomitantly elicited improved glucose tolerance.The authors discovered that betatrophin was also present in the human plasma.Surprisingly,betatrophin has been previously described by three other names,i.e.,re-feeding-induced fat and liver protein,lipasin and atypical angiopoeitin-like 8,by three independent laboratories,as nutritionally regulated liver-enriched factors that control serum triglyceride levels and lipid metabolism.Yi et al demonstration of betatrophin,as a circulating hormone that regulatesβ-cell proliferation,if successfully translated in the clinic,holds the potential to change the course of current therapies for diabetes.

Statins redux:A re-assessment of how statins lower plasma cholesterol

Obesity associated dyslipidemia and its negative effects on the heart and blood vessels have emerged as a major healthcare challenge around the globe. The use of statins, potent inhibitors of hydroxyl-methyl glutaryl(HMG) Co-A reductase, a rate-limiting enzyme in cholesterol biosynthesis, has significantly reduced the rates of cardiovascular and general mortality in patients with coronary artery disease. How statins lower plasma cholesterol levels presents a mechanistic conundrum since persistent exposure to these drugs in vitro or in vivo is known to induce overexpression of the HMG Co-A reductase gene and protein. In an attempt to solve this mechanistic puzzle, Schonewille et al, studied detailed metabolic parameters of cholesterol synthesis, interorgan flux and excretion in mice treated with 3 common statins, rosuvastatin, atorvastatin or lovastatin, each with its unique pharmacokinetics. From the measurements of the rates of heavy water(D_2O) and [^(13)C]-acetate incorporation into lipids, the authors calculated the rates of whole body and organ-specific cholesterol synthesis in control and statin-treated mice. These analyses revealed dramatic enhancement in the rates of hepatic cholesterol biosynthesis in statin-treated mice that concomitantly elicited lower levels of cholesterol in their plasma. The authors have provided strong evidence to indicate that statin treatment in mice led to induction of compensatory metabolic pathways that apparently mitigated an excessive accumulation of cholesterol in the body. It was noted however that changes in cholesterol metabolism induced by 3 statins were not identical. While sustained delivery of all 3 statins led to enhanced rates of biliary excretion of cholesterol and its fecal elimination, only atorvastatin treated mice elicited enhanced trans-intestinal cholesterol excretion. Thus, blockade of HMGCR by statins in mice was associated with profound metabolic adaptations that reset their cholesterol homeostasis. The findings of Schonewille et al, deserve to be corroborated and extended in patients in order to more effectively utilize these important cholesterol-lowering drugs in the clinic.

Bariatric surgery-mediated weight loss and its metabolic consequences for type-2 diabetes

The worldwide epidemic of obesity and its medical complications are being dealt with a combination of life style changes(e.g.,healthier diet and exercise),medications and a variety of surgical interventions.The Roux-en Y gastric bypass(RYGB) and laparoscopic adjustable gastric banding(LAGB) are two of the most common weight loss surgeries for morbid obesityassociated metabolic syndrome and insulin resistance.A vast majority of patients that undergo RYGB and LAGB are known to experience marked weight loss and attenuation of diabetes.A number of recent studies have indicated that the rates of remission in glycemic control and insulin sensitivity are significantly greater in patients that have undergone RYGB.A plausible hypothesis to explain this observation is that the gastric bypass surgery as opposed to the gastric banding procedure impinges on glucose homeostasis by a weight loss-independent mechanism.In a recent paper,Bradley et al have experimentally explored this hypothesis.The authors compared several clinical and laboratory parameters of insulin sensitivity and β-cell function in cohorts of RYGB and LAGB patients before and after they lost approximately 20% of their body mass.Afterweight loss,both groups of patients underwent similar changes in their intra-abdominal and total adipose tissue volume,hepatic triglyceride and circulating leptin levels.The RYGB patients who lost 20% body mass,manifested higher postprandial output of glucose,insulin and glucagon-like peptide-1;these laboratory parameters remained unchanged in LABG patients.Irrespective of the observed differences in transient responses of RYGB and LAGB patients to mixed meal,the overall glycemic control as judged by glucose tolerance,multi-organ insulin sensitivity and β-cell function were nearly identical in the two groups.Both RYGB and LAGB patient cohorts also experienced similar changes in the expression of a number of pro-and anti-inflammatory markers.Based on these analyses,Bradley et al concluded that similar restoration of insulin sensitivity and b-cell function in non-diabetic obese patients that have undergone RYGB and LAGB were directly due to marked weight loss.These data have important implications for the risk/benefit analysis of weight loss therapy by bariatric procedures.

Ménage-à-trois of bariatric surgery,bile acids and the gut microbiome

Bariatric surgeries have emerged as highly effective treatments for obesity associated type-2 diabetes mellitus.Evidently,the desired therapeutic endpoints such as rates of weight loss,lower levels of glycated hemoglobin and remission of diabetes are achieved more rapidly and last longer following bariatric surgery,as opposed to drug therapies alone.In light of these findings,it has been suspected that in addition to causing weight loss dependent glucose intolerance,bariatric surgery induces other physiological changes that contribute to the alleviation of diabetes.However,the putative post-surgical neuro-hormonal pathways that underpin the therapeutic benefits of bariatric surgery remain undefined.In a recent report,Ryan and colleagues shed new light on the potential mechanisms that determine the salutary effects of bariatric surgery in mice.The authors demonstrated that the improved glucose tolerance and weight loss in mice after vertical sleeve gastrectomy(VSG) surgery were likely to be caused by post-surgical changes in circulating bile acids and farnesoid-X receptor(FXR) signaling,both of which were also mechanistically linked to changes in the microbial ecology of the gut.The authors arrived at this conclusion from a comparison of genome-wide,metabolic consequences of VSG surgery in obese wild type(WT) and FXR knockout mice.Gene expression in the distal small intestines of WT and FXR knockout mice revealed that the pathways regulating bile acid composition,nutrient metabolism and anti-oxidant defense were differentially altered by VSG surgery in WT and FXR-/-mice.Based on these data Ryan et al,hypothesized that bile acid homeostasis and FXR signaling were mechanistically linked to the gut microbiota that played a role in modulating post-surgical changes in total body mass and glucose tolerance.The authors' data provide a plausible explanation for putative weight loss-independent benefits of bariatric surgery and its relationship with metabolism of bile acids.

Metabolic balancing acts of vitamin A in type-2 diabetes and obesity

Using mice that lack retinaldehyde dehydrogenase 1 gene(Raldh1-/-mice),Kierfer et al demonstrated that retinoids(metabolites of Vitamin A) play an important role in the regulation of cellular metabolisms and energetics.The Aldh1a1-/-mice were leaner and less prone to accumulate subcutaneous and visceral fat,and to acquire insulin resistance on high fat diet.Their lower fasting glucose levels concomitant with reduced hepatic expression of glucose 6-phosphatase and phosphoenol pyruvate carboxy kinase genes indicated that Aldh1a1-/-mice were defective in gluconeogenesis.These mice also had lower plasma levels of triglycerides,very low-density lipoprotein and lowdensity lipoprotein-triacylglycerol,while their skeletal muscles elicited higher expression of carnitine palmatoyl transferase,medium chain acyl-A dehydrogenase,peroxisome proliferation activated receptor(PPARα and PPARδ.Thus,the improved lipid and lipoprotein profiles of Raldh1a1-/-mice resulted from a combination of reduced lipogenesis and enhanced fatty acid oxidation by retinoids.The mechanistic details of how retinoids integrate fasting glucose,hepatic gluconeogenesis and adaptive thermogenesis independent of body mass deserve further study.

Gestational 营养和肥胖的发展在成人生活期间

Recent epidemiological studies indicate a strong linkbetween intrauterine under-nutrition and propensityof such off spring for developing obesity and meta-bolic syndrome in later life. Garg et al investigated the mechanistic basis of this phenomenon and its potential reversibility in rats. The authors found that rats experiencing gestational under-nutrition but fed normally after birth (IUGR) gained body mass with excessive subcutaneous and visceral fat. The IUGR rats were alsome tabolically inflexible since they showed similar rates of energy expenditure and O2consumption in the fedand fasted states. However, if such pups were food-restricted during lactation (PNGR), their metabolic profiles resembled those of control and IPGR (subject tofood restriction during pre- and postnatal periods) rats.Thus, postnatal caloric restriction superimposed on intrauterine under nutrition significantly improved insulinsensitivity and adiposity of rats that would otherwise develop metabolic inflexibility and visceral obesity. The observations of Garg et al , have serious implications interm of the design of the future experimental studiesas well as their clinical translation in humans.

Circadian rhythms of hormone secretion and obesity

The adipose tissue homeostasis is profoundly affected by circadian rhythms of corticosteroid secretion and chronic loss of hormonal oscillations is associated with obesity. How adipose tissue differentially responds to pulsatile vs continuous presence of glucocorticoids is poorly defined. To address this question, Bahrami-Nejad et al studied differentiation of pre-adipocytes, containing endogenously tagged CCAAT/enhancer binding protein and peroxisome proliferator-activated receptor(PPAR) γ(key regulators of adipocyte differentiation), in response to corticosteroids that were delivered either in an oscillatory fashion or continuously. The authors show that the bi-stable state of differentiation of pre-adipocytes and adipocytes was regulated by a combination of fast and slow positive feedback networks, that determined unique threshold of PPARγ in these cells. Evidently, pre-adipocytes used the fast feedback loop to reject differentiation cues of oscillating pulses of glucocorticoids and failed to differentiate into fat cells. In contrast, when glucocorticoids were delivered continuously, precursor cells exploited the slow feedback loop to embark on a path of maximal differentiation. This differential differentiation response of pre-adipocytes to pulsatile vs continuous exposure to glucocorticoids was corroborated in vivo. Thus, mice receiving non-oscillating doses of exogenous glucocorticoids, for 21 d, elicited excessive accumulation of visceral and subcutaneous fat. These data shed new light on the mechanisms of obesity caused by putative misalignment of circadian secretion of glucocorticoids or their persistently high levels due to chronic stress or Cushing's disease.

Gut-brain crosstalk regulates craving for fatty food

Patients undergoing Roux-en-Y gastric bypass(RYGB)surgery elicit striking loss of body weight. Anatomical restructuring of the gastrointestinal(GI) tract, leading to reduced caloric intake and changes in food preference, are thought to be the primary drivers of weight loss in bariatric surgery patients. However, the mechanisms by which RYGB surgery causes a reduced preference for fatty foods remain elusive. In a recent report, Hankir et al described how RYGB surgery modulated lipid nutrient signals in the intestine of rats to blunt their craving for fatty food. The authors reported that RYGB surgery restored an endogenous fat-satiety signaling pathway, mediated via oleoylethanolamide(OEA), that was greatly blunted in obese animals. In RYGB rats, high fat diet(HFD) led to increased production of OEA that activated the intestinal peroxisome proliferation activator receptors-α(PPARα). In RYGB rats, activation of PPARα by OEA was accompanied by enhanced dopamine neurotransmission in the dorsal striatum and reduced preference for HFD. The authors showed that OEA-mediated signals to the midbrain were transmitted via the vagus nerve. Interfering with either the production of OEA in enterocytes, or blocking of vagal and striatal D1 receptors signals eliminated the decreased craving for fat in RYGB rats. These studies demonstrated that bariatric surgery led to alterations in the reward circuitry of the brain in RYGB rats and reduced their preference for HFD.