The Portal Theory Supported by Venous Drainage–Selective Fat Transplantation

OBJECTIVE The "portal hypothesis" proposes that the liver is directly exposed to free fatty acids and cytokines increasingly released from visceral fat tissue into the portal vein of obese subjects, thus rendering visceral fat accumulation particularly hazardous for the development of hepatic insulin resistance and type 2 diabetes. In the present study, we used a fat transplantation paradigm to (artificially) increase intra-abdominal fat mass to test the hypothesis that venous drainage of fat tissue determines its impact on glucose homeostasis. RESEARCH DESIGN AND METHODS Epididymal fat pads of C57Bl6/J donor mice were transplanted into littermates, either to the parietal peritoneum (caval/systemic venous drainage) or, by using a novel approach, to the mesenterium, which confers portal venous drainage. RESULTS Only mice receiving the portal drained fat transplant developed impaired glucose tolerance and hepatic insulin resistance. mRNA expression of proinflammatory cytokines was increased in both portally and systemically transplanted fat pads. However, portal vein (but not systemic) plasma levels of interleukin (IL)-6 were elevated only in mice receiving a portal fat transplant. Intriguingly, mice receiving portal drained transplants from IL-6 knockout mice showed normal glucose tolerance. CONCLUSIONS These results demonstrate that the metabolic fate of intra-abdominal fat tissue transplantation is determined by the delivery of inflammatory cytokines to the liver specifically via the portal system, providing direct evidence in support of the portal hypothesis

Short-term HFD does not alter lipolytic function of adipocytes

A short bout of high fat diet (HFD) impairs glucose tolerance and hepatic insulin sensitivity. We recently identified adipose tissue inflammation and resulting dysfunctional adipose tissue-liver cross-talk as an early event in the development of HFD-induced hepatic insulin resistance. In particular, reducing white adipose tissue (WAT) inflammation by adipocyte-specific depletion of Fas/CD95 protected mice from developing hepatic insulin resistance but not hepatic steatosis. Herein, we expanded our previous work and determined the impact of four days of HFD on lipolytic activity of isolated adipocytes. Compared with chow-fed mice, the degree of basal and isoproterenol-stimulated free fatty acid (FFA) and glycerol release was similar in HFD-fed animals. Moreover, insulin's ability to suppress lipolysis remained intact, suggesting retained insulin sensitivity. Despite unaltered lipolysis, circulating FFA concentrations were greatly increased in non-fasted HFD-fed mice. In conclusion, a short-term HFD challenge does not affect lipolytic function of adipocytes. The observed increase of circulating FFA levels in randomly fed animals may rather be the result of increased dietary fat supply

Uniparental disomy 7 in Silver—Russell syndrome and primordial growth retardation

Maternal uniparental disomy for the entire chromosome 7 has so far been reported in three patients with intrauterine and postnatal growth retardation. Two were detected because they were homozygous for a cystic fibrosis mutation for which only the mother was heterozygous, and one because he was homozygous for a rare COL1A2 mutation. We investigated 35 patients with either the Silver-Russell syndrome or primordial growth retardation and their parents with PCR markers to search for uniparental disomy 7. Four of 35 patients were found to have maternal disomy, including three with isodisomy and one with heterodisomy. The data confirm the hypothetical localization of a maternally imprinted gene (or more than one such gene) on chromosome 7. It is suggested to search for UPD 7 in families with an offspring with sporadic Silver-Russell syndrome or primordial growth retardatio

Fas and FasL expression in human adipose tissue is related to obesity, insulin resistance, and type 2 diabetes

Context: Deletion of the death receptor Fas (CD95) in adipocytes of mice is associated with improved insulin sensitivity and reduced adipose tissue (AT) inflammation. Objective: Here we investigate the relationship of AT Fas with human obesity. Design and Methods: In paired samples of omental and sc AT from 256 lean and obese (including insulin-sensitive and insulin-resistant subgroups; n = 60) participants, we investigated whether Fas and Fas-ligand (FasL) mRNA expression is fat depot-specific, altered in obesity, and related to measures of AT inflammation and insulin sensitivity. In addition, AT Fas mRNA expression was measured in 16 obese patients after significant weight loss of 45 ± 6.3 kg in the context of a two-step bariatric surgery strategy. Results: Fas and FasL are significantly higher expressed in omental (OM) compared to sc AT. Fas expression correlates with body mass index (OM, r(2) = 0.44; sc, r(2) = 0.14), AT macrophage infiltration (OM, r(2) = 0.36; sc, r(2) = 0.16), and glucose infusion rate in euglycemic-hyperinsulinemic clamps (OM, r(2) = 0.17; sc, r(2) = 0.13) (P < .05 for all). FasL expression most strongly correlates with adipocyte size (OM, r(2) = 0.32; sc, r(2) = 0.17) and AT macrophage infiltration (OM, r(2) = 0.46; sc, r(2) = 0.02). Insulin-sensitive obese individuals had significantly lower Fas and FasL expression than insulin-resistant obese individuals. Significant weight loss 12 months after gastric sleeve resection is associated with a significantly reduced Fas expression in OM and sc fat depots. Conclusions: Independently of body weight, increased Fas expression may contribute to impaired insulin sensitivity and AT dysfunction in obesity. Moreover, significant weight loss reduces Fas expression in OM and sc fat depots

Opposing effects of reduced kidney mass on liver and skeletal muscle insulin sensitivity in obese mice

Reduced kidney mass and/or function may result in multiple metabolic derangements, including insulin resistance. However, underlying mechanisms are poorly understood. Herein, we aimed to determine the impact of reduced kidney mass on glucose metabolism in lean and obese mice. To that end, seven-week-old C57BL6/J mice underwent uninephrectomy (UniNx) or sham operation. After surgery, animals were fed either a chow (standard) or a high fat diet (HFD) and glucose homeostasis was assessed 20 weeks after surgery. Intraperitoneal glucose tolerance was similar in sham-operated and UniNx mice. However, insulin-stimulated glucose disposal in vivo was significantly diminished in UniNx mice, whereas insulin-stimulated glucose uptake into isolated skeletal muscle was similar in sham-operated and UniNx mice. Of note, capillary density was significantly reduced in skeletal muscle of HFD-fed UniNx mice. In contrast, hepatic insulin sensitivity was improved in UniNx mice. Furthermore, adipose tissue HIF1α-expression and inflammation was reduced in HFD-fed UniNx mice. Treatment with the angiotensin II receptor blocker telmisartan improved glucose tolerance and hepatic insulin sensitivity in HFD-fed sham-operated but not UniNx mice. In conclusion, UniNx protects from obesity-induced adipose tissue inflammation and hepatic insulin resistance but it reduces muscle capillary density and, thus, deteriorates HFD-induced skeletal muscle glucose disposal

Clinical follow-up of the first SF-1 insufficient female patient

Steroidogenic factor 1 (SF-1/NR5A1) plays a crucial role in regulating adrenal development, gonad determination and differentiation, and in the hypothalamic-pituitary control of reproduction and metabolism. In men (46, XY), it is known that mutations in SF-1/NR5A1 gene cause a wide phenotypic spectrum with variable degrees of undervirilization. In recent years, the role of SF-1 in the ovarian function was increasingly discussed and alterations in the gene were related to primary ovarian insufficiency. We describe the follow-up of a 46, XX affected woman with a SF-1 mutation and by comparing our case with the known manifestations reported in the literature, we try to further elucidate the function of SF-1 in the ovary. During infancy, adrenal insufficiency was the only clinical sign of the loss-of-function as ovarian development and function seemed normal. To date, this young woman aged 16.5 years shows normal growth, normal BMI and psychomotor development, has a normal puberty and regular menstruation. This report shows one, to date uniquely described, phenotypic variant of SF-1 mutation in a 46, XX affected person with adrenocortical insufficiency but no ovarian dysfunction nor disturbance of pubertal development. To follow the natural history of SF-1 mutation in a 46, XX individual will further shed light on its role in the ovarian function and thus will help to counsel affected patients in future

Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies

Peer reviewe

Adipose tissue inflammation contributes to short-term high-fat diet-induced hepatic insulin resistance

High-fat feeding for 3-4 days impairs glucose tolerance and hepatic insulin sensitivity. However, it remains unclear whether the evolving hepatic insulin resistance is due to acute lipid overload or the result of induced adipose tissue inflammation and consequent dysfunctional adipose tissue-liver cross-talk. In the present study, feeding C57Bl6/J mice a fat-enriched diet [high-fat diet (HFD)] for 4 days induced glucose intolerance, hepatic insulin resistance (as assessed by hyperinsulinemic euglycemic clamp studies), and hepatic steatosis as well as adipose tissue inflammation (i.e., TNFα expression) compared with standard chow-fed mice. Adipocyte-specific depletion of the antiapoptotic/anti-inflammatory factor Fas (CD95) attenuated adipose tissue inflammation and improved glucose tolerance as well as hepatic insulin sensitivity without altering the level of hepatic steatosis induced by HFD. In summary, our results identify adipose tissue inflammation and resulting dysfunctional adipose tissue-liver cross-talk as an early event in the development of HFD-induced hepatic insulin resistance