Metreleptin therapy for nonalcoholic steatohepatitis: Open-label therapy interventions in two different clinical settings.

BACKGROUND: Recombinant leptin therapy reverses nonalcoholic steatohepatitis (NASH) in leptin-deficient lipodystrophy. We inquired if leptin therapy would improve nonalcoholic steatohepatitis in more common forms of this heterogeneous condition. METHODS: Nine male patients with relative leptin deficiency (level < 25th percentile of body mass index- and gender-matched United States population) and biopsy-proven NASH and 23 patients with partial lipodystrophy and NASH were recruited for two distinctive open-label trials. Participants received leptin therapy in the form of metreleptin for 12 months. The primary endpoints were the global nonalcoholic steatohepatitis scores from paired liver biopsies scored blindly. FINDINGS: Of 9 participants recruited in the relative leptin deficiency treatment study, 7 completed 12-months of therapy. Mean global NASH scores were reduced from 8 ± 3 to 5 ± 2 (range: from 1 to 6, P = 0.004). In the partial lipodystrophy study, 19 of 22 subjects completed 12 months of treatment, and 18 completed a second liver biopsy. Global NASH scores also reduced significantly from 6 ± 2 to 5 ± 2 (range: from -2 to 4, P = 0.008). In both studies, the predominant changes were in steatosis and hepatic injury scores. CONCLUSION: Our findings show that patients with NASH associated with both relative leptin deficiency and partial lipodystrophy have reductions in hepatic steatosis and injury in response to exogenous leptin therapy. Moreover, leptin deficiency may have regulatory effects in mediating fat deposition and ensuing injury in the liver.TRIAL REGISTRATION. ClinicalTrials.gov NCT00596934 and NCT01679197.

Hungry bone syndrome secondary to prostate cancer successfully treated with radium therapy.

A 50-year-old man with a history of prostate cancer with extensive bone metastasis and hypocalcaemia presented with muscle aches and cramps. Physical exam was significant for Chvostek's and Trousseau's sign. Laboratory assessment was consistent with profound hypocalcaemia. This was believed to be due to hungry bone syndrome secondary to advanced prostate cancer. He was treated with intravenous calcium, vitamin D and calcitriol. He also received three doses of radium223 therapy. After therapy, hypocalcaemic episodes resolved. Follow-up after 2.5 years showed continued resolution of hypocalcaemia.

Metabolic Parameters, Weight Loss, and Comorbidities 4 Years After Roux-en-Y Gastric Bypass and Sleeve Gastrectomy.

BACKGROUND: Sleeve gastrectomy (LSG) is now the predominant bariatric surgery performed, yet there is limited long-term data comparing important outcomes between LSG and Roux-en-Y gastric bypass (RYGB). This study compares weight loss and impact on comorbidities of the two procedures. METHODS: We retrospectively evaluated weight, blood pressure, hemoglobin A1c, cholesterol, and medication use for hypertension, diabetes, and hyperlipidemia at 1-4 years post-operatively in 380 patients who underwent RYGB and 334 patients who underwent LSG at the University of Michigan from January 2008 to November 2013. Follow-up rates from 714 patients initially were 657 (92%), 556 (78%), 507 (71%), and 498 (70%) at 1-4 years post-operatively. RESULTS: Baseline characteristics were similar except for higher weight and BMI in LSG. There was greater weight loss with RYGB vs. LSG at all points. Hemoglobin A1c and total cholesterol improved more in RYGB vs. LSG at 4 years. There was greater remission of hypertension and discontinuation of all medications for hypertension and diabetes with RYGB at 4 years. CONCLUSIONS: Weight loss, reduction in medications for hypertension and diabetes, improvements in markers of diabetes and hyperlipidemia, and remission rates of hypertension were superior with RYGB vs. LSG 4 years post-operatively. Choice of bariatric procedures should be tailored to surgical risk, comorbidities, and weight loss goals.

Osteitis fibrosa cystica masquerading as bone neoplasm.

A 50-year-old female patient with no significant medical history presented with left knee pain. Radiographs of the knee showed a circumferential swelling of the distal femur suggestive of neoplasia. Further evaluation revealed multiple lesions in the left iliac bone and proximal femur. Biopsy was suggestive of a reparative granuloma or an aneurysmal bone cyst. Laboratory assessment showed hypercalcaemia and elevated parathyroid hormone consistent with severe primary hyperparathyroidism. Osseous survey was significant for salt and pepper appearance of the skull. Ultrasound of the neck and 99mTc-sestamibi parathyroid scintigraphy localised a left parathyroid adenoma/carcinoma. Parathyroidectomy was successful, and a large parathyroid adenoma was excised. Six months later, the patient was doing fine with her gait returning to normal. On follow-up 2 years later, she had no recurrence of the lesions.

Milestone Weight Loss Goals (Weight Normalization and Remission of Obesity) after Gastric Bypass Surgery: Long-Term Results from the University of Michigan.

BACKGROUND: Rates of weight normalization and obesity remission after Roux-en-Y gastric bypass (GB) are unknown. This study evaluated weight loss, rates of achieving body mass index (BMI) <25 or 30 kg/m2, recidivism, and predictors of success following GB. METHODS: We retrospectively studied weight and BMI at baseline, 2 and 6 months, and annually at 1-7 years in 219 patients undergoing GB at the University of Michigan from January 2008 to November 2010. RESULTS: Follow-up was excellent for a population traditionally associated with high attrition rates with data availability of 157/219, 145/219, 144/219, 134/219, 123/219, 82/161, and 29/64 patients at 1-7 years, respectively. Mean baseline BMI was 47.0 kg/m2. Weight normalization (BMI <25 kg/m2) occurred in 2.3-6.8% of patients. More importantly, 47% of patients achieved remission of obesity (BMI <30 kg/m2) at some time point and 24% (52/219) at the last observed time point. BMI <30 kg/m2 was associated with a lower initial BMI and follow-up for more than 2 years. CONCLUSIONS: Rates of weight normalization are low after GB; however, a large number of patients achieved BMI <30 kg/m2. While the percent total weight loss and excess weight loss are both quite high in the entire cohort and this is likely associated with significant health benefits, our results still underscore the need to address obesity with intensive clinical attention earlier in its course.

Roux-En-Y Gastric Bypass Vs. Sleeve Gastrectomy: Balancing the Risks of Surgery with the Benefits of Weight Loss.

BACKGROUND: The purpose of the study was to compare weight loss, metabolic parameters, and postoperative complications in patients undergoing Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG). METHODS: We retrospectively studied 30-day postoperative complications as well as change in weight, blood pressure, cholesterol, hemoglobin, hemoglobin A1C, and creatinine from baseline to 2, 6, 12, and 24 months postoperatively in 383 patients undergoing GB and 336 patients undergoing SG at the University of Michigan from January 2008 to November 2013. For a study population which typically has high attrition rates, there were excellent follow-up rates (706/719 at 2 months, 566/719 at 6 months, 519/719 at 12 months, and 382/719 at 24 months). RESULTS: Baseline characteristics were similar in both groups except for higher weight and BMI in the SG group. The GB group experienced greater total body weight loss at 6, 12, and 24 months (41.9 vs. 34.6 kg at 24 months, p < 0.0001). Excess weight loss was 69.7 and 51.7 % following GB and SG respectively at 24 months (p < 0.0001). BP improved significantly in both groups. Surgical complication rates were greater after GB (10.1 vs. 3.5 %, p = 0.0007) with no significant difference in life-threatening or potentially life-threatening complications. CONCLUSIONS: Weight loss was greater following GB compared to SG at 2 years. The risk for surgical complications was greater following GB. Surgical intervention should be tailored to surgical risk, comorbidities, and desired weight loss.

Retinoic acid regulates several genes in bile acid and lipid metabolism via upregulation of small heterodimer partner in hepatocytes.

Retinoic acid (RA) affects multiple aspects of development, embryogenesis and cell differentiation processes. The liver is a major organ that stores RA suggesting that retinoids play an important role in the function of hepatocytes. In our previous studies, we have demonstrated the involvement of small heterodimer partner (SHP) in RA-induced signaling in a non-transformed hepatic cell line AML 12. In the present study, we have identified several critical genes in lipid homeostasis (Apoa1, Apoa2 and ApoF) that are repressed by RA-treatment in a SHP dependent manner, in vitro and also in vivo with the use of the SHP null mice. In a similar manner, RA also represses several critical genes involved in bile acid metabolism (Cyp7a1, Cyp8b1, Mdr2, Bsep, Baat and Ntcp) via upregulation of SHP. Collectively our data suggest that SHP plays a major role in RA-induced potential changes in pathophysiology of metabolic disorders in the liver.

Alterations in lipid signaling underlie lipodystrophy secondary to AGPAT2 mutations.

Congenital generalized lipodystrophy (CGL), secondary to AGPAT2 mutation is characterized by the absence of adipocytes and development of severe insulin resistance. In the current study, we investigated the adipogenic defect associated with AGPAT2 mutations. Adipogenesis was studied in muscle-derived multipotent cells (MDMCs) isolated from vastus lateralis biopsies obtained from controls and subjects harboring AGPAT2 mutations and in 3T3-L1 preadipocytes after knockdown or overexpression of AGPAT2. We demonstrate an adipogenic defect using MDMCs from control and CGL human subjects with mutated AGPAT2. This defect was rescued in CGL MDMCs with a retrovirus expressing AGPAT2. Both CGL-derived MDMCs and 3T3-L1 cells with knockdown of AGPAT2 demonstrated an increase in cell death after induction of adipogenesis. Lack of AGPAT2 activity reduces Akt activation, and overexpression of constitutively active Akt can partially restore lipogenesis. AGPAT2 modulated the levels of phosphatidic acid, lysophosphatidic acid, phosphatidylinositol species, as well as the peroxisome proliferator-activated receptor γ (PPARγ) inhibitor cyclic phosphatidic acid. The PPARγ agonist pioglitazone partially rescued the adipogenic defect in CGL cells. We conclude that AGPAT2 regulates adipogenesis through the modulation of the lipome, altering normal activation of phosphatidylinositol 3-kinase (PI3K)/Akt and PPARγ pathways in the early stages of adipogenesis.

The CD40-autophagy pathway is needed for host protection despite IFN-Γ-dependent immunity and CD40 induces autophagy via control of P21 levels.

Autophagy degrades pathogens in vitro. The autophagy gene Atg5 has been reported to be required for IFN-γ-dependent host protection in vivo. However, these protective effects occur independently of autophagosome formation. Thus, the in vivo role of classic autophagy in protection conferred by adaptive immunity and how adaptive immunity triggers autophagy are incompletely understood. Employing biochemical, genetic and morphological studies, we found that CD40 upregulates the autophagy molecule Beclin 1 in microglia and triggers killing of Toxoplasma gondii dependent on the autophagy machinery. Infected CD40(-/-) mice failed to upregulate Beclin 1 in microglia/macrophages in vivo. Autophagy-deficient Beclin 1(+/-) mice, mice with deficiency of the autophagy protein Atg7 targeted to microglia/macrophages as well as CD40(-/-) mice exhibited impaired killing of T. gondii and were susceptible to cerebral and ocular toxoplasmosis. Susceptibility to toxoplasmosis occurred despite upregulation of IFN-γ, TNF-α and NOS2, preservation of IFN-γ-induced microglia/macrophage anti-T. gondii activity and the generation of anti-T. gondii T cell immunity. CD40 upregulated Beclin 1 and triggered killing of T. gondii by decreasing protein levels of p21, a molecule that degrades Beclin 1. These studies identified CD40-p21-Beclin 1 as a pathway by which adaptive immunity stimulates autophagy. In addition, they support that autophagy is a mechanism through which CD40-dependent immunity mediates in vivo protection and that the CD40-autophagic machinery is needed for host resistance despite IFN-γ.

Role of FoxO1 in FFA-induced oxidative stress in adipocytes.

Reactive oxygen species (ROS) production has recently been established as an essential contributor in the pathogenesis of obesity-associated insulin resistance. The FoxO1 pathway plays a role not only in nutrient sensing but also in regulating ROS production. We exposed adipocytes to free fatty acids (FFA) and demonstrated that FoxO1 protein levels decrease in a dose-dependent manner. The FoxO1 downregulation correlated with an increase in the production of ROS and a proinflammatory adipokine pattern characterized by a decrease in adiponectin and an increase in IL-6, plasminogen activator inhibitor-1, and monocyte chemotactic protein-1 mRNA expression levels. Similarly, a decrease in FoxO1 protein levels was seen in adipocytes of db/db mice compared with controls. Treatment with the sirtuin agonist resveratrol, which translocates FoxO1 to the nucleus, increased FoxO1 protein levels in adipocytes exposed to FFA. This correlated with a decrease in the generation of ROS and a partial reversal of the proinflammatory adipokine pattern. Together these results indicate that the insulin-resistant adipocyte produced by the exposure to a high concentration of fatty acids is characterized by decreased levels of FoxO1. These data also suggest that modulation of the Sirt1/FoxO1 pathway is a potentially useful therapeutic target for the obesity-induced dysfunctional adipocyte.

Role of CD40-dependent down-regulation of CD154 in impaired induction of CD154 in CD4(+) T cells from HIV-1-infected patients.

CD40-CD154 interaction is pivotal for cell-mediated immunity. There are contradictory reports on whether HIV-1 infection impairs CD154 induction. The interaction between CD40 and CD154 is important not only because it results in activation of APCs but also because it controls CD154 by diminishing expression of this molecule. Compared with healthy controls, CD4(+) T cells from HIV-1(+) patients had impaired induction of CD154 when T cell activation was mediated by CD40(+) APCs. In contrast, T cell activation in the absence of these cells resulted in normal CD154 expression. CD154 induction in HIV-1(+) patients and controls were similar upon blockade of CD40-CD154 binding. Defective regulation of CD154 appeared to occur downstream of the control of mRNA levels because up-regulation of CD154 mRNA was not impaired by HIV-1 infection. This work identifies CD40 as a mediator of impaired CD154 induction in HIV-1 infection and explains why this defect was not detected by studies where T cell activation was triggered independently of CD40(+) APCs. In addition, dysregulation of CD154 in HIV-1 infection likely contributes to immunodeficiency because diminished expression of CD154 induced by CD40 is of functional relevance, resulting in decreased dendritic cell maturation.