Jeffrey S. Flier

Obesity is closely associated with the metabolic syndrome, a combination of disorders including insulin resistance, diabetes, dyslipidemia, and hypertension. A role for local glucocorticoid reamplification in obesity and the metabolic syndrome has been suggested. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active cortisol from inactive 11-keto forms, and aP2-HSD1 mice with relative transgenic overexpression of this enzyme in fat cells develop visceral obesity with insulin resistance and dyslipidemia. Here we report that aP2-HSD1 mice also have high arterial blood pressure (BP). The mice have increased sensitivity to dietary salt and increased plasma levels of angiotensinogen, angiotensin II, and aldosterone. This hypertension is abolished by selective angiotensin II receptor AT-1 antagonist at a low dose that does not affect BP in non-Tg littermates. These findings suggest that activation of the circulating renin-angiotensin system (RAS) develops in aP2-HSD1 mice. The long-term hypertension is further reflected by an appreciable hypertrophy and hyperplasia of the distal tubule epithelium of the nephron, resembling salt-sensitive or angiotensin II–mediated hypertension. Taken together, our findings suggest that overexpression of 11β-HSD1 in fat is sufficient to cause salt-sensitive hypertension mediated by an activated RAS. The potential role of adipose 11β-HSD1 in mediating critical features of the metabolic syndrome extends beyond obesity and metabolic complications to include the most central cardiovascular feature of this disorder.

Working out the intricate pathways that regulate energy balance has kept biologists busy for decades. The part played by the hypothalamus and fat cells in energy balance has been well worked out, but the importance of intracellular intermediates such as malonyl CoA has been less well defined. In their Perspective, Ruderman and Flier discuss new findings in knockout mice deficient in one isoform of the enzyme ACC, which synthesizes malonyl CoA ( Abu-Elheiga et al.). The new work shows that malonyl CoA, specifically synthesized by this ACC isoform, is an important regulator of fatty acid oxidation, and that its absence results in mice that massively overeat yet never gain weight.

Obesity in humans and in rodents is usually associated with high circulating leptin levels and leptin resistance. To examine the molecular basis for leptin resistance, we determined the ability of leptin to induce hypothalamic STAT3 (signal transducer and activator of transcription) signaling in C57BL/6J mice fed either low-fat or high-fat diets. In mice fed the low-fat diet, leptin activated STAT3 signaling when administered via the intraperitoneal (ip) or the intracerebroventricular (icv) route, with the half-maximal dose being 30-fold less when given by the icv route. The high-fat diet increased body-weight gain and plasma leptin levels. After 4 weeks on the diet, hypothalamic STAT3 signaling after ip leptin administration was equivalent in both diet groups. In contrast, peripherally administered leptin was completely unable to activate hypothalamic STAT3 signaling, as measured by gel shift assay after 15 weeks of high-fat diet. Despite the absence of detectable signaling after peripheral leptin at 15 weeks, the mice fed the high-fat diet retained the capacity to respond to icv leptin, although the magnitude of STAT3 activation was substantially reduced. These results suggest that leptin resistance induced by a high-fat diet evolves during the course of the diet and has at least two independent causes: an apparent defect in access to sites of action in the hypothalamus that markedly limits the ability of peripheral leptin to activate hypothalamic STAT signaling, and an intracellular signaling defect in leptin-responsive hypothalamic neurons that lies upstream of STAT3 activation.

▪ Abstract The discovery of the adipose-derived hormone leptin has generated enormous interest in the interaction between peripheral signals and brain targets involved in the regulation of feeding and energy balance. Plasma leptin levels correlate with fat stores and respond to changes in energy balance. It was initially proposed that leptin serves a primary role as an anti-obesity hormone, but this role is commonly thwarted by leptin resistance. Leptin also serves as a mediator of the adaptation to fasting, and this role may be the primary function for which the molecule evolved. There is increasing evidence that leptin has systemic effects apart from those related to energy homeostasis, including regulation of neuroendocrine and immune function and a role in development.

We evolved to live in a world in which food supplies are unpredictable in availability and often insufficient to meet immediate needs. Consequently, it is critical to be able to switch between the distinct metabolic programs that are appropriate to either the fasted or the fed state. Although many endocrine systems are involved in this transition, insulin is a preeminent hormonal mediator of this nutritional switch. Insulin levels rise postprandially to mediate anabolism and energy storage and fall between meals to permit the release of adipose energy stores and the switch from glucose use to production. The relevant actions of insulin take place in adipose tissue, muscle, and liver, where insulin receptor signaling exerts tissue-specific effects on an array of metabolic pathways that impact on carbohydrate, lipid, and protein metabolism. The cellular mechanism of insulin action has been a topic of major interest for many years. The greatest emphasis has been on the early steps of signal transduction, involving the insulin receptor substrate (IRS) proteins, which when tyrosine phosphorylated by the insulin receptor kinase serve as docking proteins for assembly of signaling complexes for downstream pathways such as ras-mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and others (1). Many classic actions of insulin (e.g., glucose transport and glycogen synthesis) occur very rapidly and require the mediation of rapid changes in the state of protein phosphorylation or dephosphorylation. It is established that, alongside these rapid nongenomic effects, changes in gene expression play critical roles in insulin action in adipose cells, liver, and other tissues (2). Although insulin-responsive DNA elements have been identified in the promoters of several insulin-regulated genes, the identity of transcription factors responsible for mediating key insulin actions on gene expression has been, until recently, obscure. Two recent papers in PNAS (3, 4) provide important new information on the …

The expression of leptin, an adipocyte-derived protein whose circulating levels reflect energy stores, can be induced by tumor necrosis factor (TNF)alpha in rodents, but an association between the TNF alpha system and leptin levels has not been reported in humans. To evaluate the potential association between serum leptin and the TNF alpha system, we measured the levels of soluble TNF alpha-receptor (sTNF alpha-R55), which has been validated as a sensitive indicator of activation of the TNF alpha system. We studied two groups: 1) 82 young healthy normal controls and 2) 48 patients with noninsulin dependent diabetes mellitus (NIDDM) and 24 appropriately matched controls. By simple regression analysis in controls, there was a strong positive association between leptin and 3 parameters: body mass index, sTNF alpha-R55, and insulin levels. In a multiple regression analysis model, leptin remained significantly and strongly associated with body mass index, and the association of leptin with both insulin and sTNF alpha-R55, although weakened, remained significant. Patients with NIDDM had leptin concentrations similar to controls of similar weight. Importantly, serum levels of sTNF alpha-R55 were also positively and independently associated with leptin in this group of diabetic subjects and matched controls. These data are consistent with the hypothesis that the TNF alpha system plays a role in regulating leptin levels in humans. Further elucidation of a possible role of the TNF alpha system in leptin expression and circulating levels may have important implications for our understanding of obesity and cachexia in humans.