In This Issue of Diabetes Open Access

Data is this issue of Diabetes (p. 4089) show that brown adipose tissue (BAT) plays a key role in both glucose metabolism and insulin sensitivity in humans. Although growing interest in the potential value of BAT for combating diabetes and other metabolic diseases lies in this tissue’s ability to dissipate energy as heat, much of the existing work on BAT’s function has been in rodents, leaving its role in humans poorly understood. Addressing this lack of knowledge, the newly published report focused on 12 men who were categorized as either BAT⁺ or BAT^- based on ¹⁸F-FDG disposal using positron emission tomography/computed tomography scans. Men in the BAT⁺ group had mean BAT volume of 69 mL, compared with 4 mL in the BAT^- group. Participants’ resting energy expenditure (REE) and substrate oxidation were studied under both cold exposure (CE) and thermoneutral conditions to determine whether these parameters differed between the groups. Importantly, the investigators ensured that the CE did not induce shivering, thereby isolating the potential effect of BAT on key outcomes independent of the potentially confounding impact of shivering. The results showed that CE increased REE by 15% in the BAT⁺ group only, a finding that points to a relationship between activation of this tissue and increased REE. Importantly, plasma-derived glucose oxidation and free fatty acid oxidation accounted for approximately 30% and 70% of the observed increases in REE, respectively. The new report also demonstrated that in the BAT⁺ group, CE increased whole-body glucose disposal, suggesting that this tissue has a role in glucose regulation by promoting uptake of glucose from the circulation. Indeed, these data support the idea that about 70 mL of BAT—the average volume in the BAT⁺ group—can remove a significant amount of glucose from the circulation, a finding that offers substantial forward movement to this important line of research. — Helaine E. Resnick, PhD, MPH

Chondronikola et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes 2014;63:4089–4099

Identifying actionable links in the causal pathway between obesity and insulin resistance remains a significant challenge in diabetes research. Potentially groundbreaking work by Wang et al. in this issue of Diabetes (p. 4172) suggests that myeloperoxidase (MPO) can be a trigger for obesity-associated insulin resistance, and that inhibition of MPO may offer novel pathways forward in the fight against obesity and obesity-related disease. MPO—a protein expressed by neutrophils—produces pro-oxidants like hypochlorous acid, which are normally used by neutrophils arriving at infection sites to combat bacteria and other pathogenic agents. In the early stages of obesity, however, neutrophils infiltrate adipose tissue where they can promote inflammatory processes. In this new work, investigators fed mice either a normal diet (ND) or a high-fat diet (HFD) for 16 weeks and then conducted careful studies of the resulting adipose tissue. In addition to the expected weight gain, the HFD group showed elevated expression of MPO proteins in white adipose tissue (WAT) and a worsening of insulin sensitivity. Peroxidase activity in epididymal WAT was significantly higher for HFD mice, and the source of this activity was attributed primarily to the accumulation of neutrophils (a 15-fold increase in peroxidase activity relative to controls). Peroxidase activity in monocytes and macrophages was less remarkable with 3.5- and 1.7-fold increases, respectively. Experiments involving knockout mice deficient in the MPO gene (MPO^-/-) revealed several dramatic effects of MPO removal relative to wild-type (WT) controls: By enhancing mitochondrial activity in brown adipose tissue (BAT) and raising body temperature, MPO deficiency reduced the HFD-related tendency toward obesity. A molecular mechanism that could explain the reduced weight gain in MPO^-/- HFD mice was the significantly higher levels of uncoupling protein 1 in BAT observed in these mice. Furthermore, cytokine mRNA isolated from WAT of MPO^-/- mice showed lower levels of HFD-associated proinflammatory cytokines after 6 weeks of an HFD. Finally, after 16 weeks of an HFD, glucose tolerance testing showed that MPO^-/- mice had a muted response that fell between those of WT-HFD and WT-ND, and MPO^-/- mice also exhibited less insulin resistance as measured by insulin tolerance tests. Taken together, the new data suggest that deactivating MPO is a potentially useful strategy for slowing obesity and lowering the associated risks for diabetes pathogenesis. — Wendy Chou, PhD

Wang et al. Myeloperoxidase deletion prevents high-fat diet–induced obesity and insulin resistance. Diabetes 2014;63:4172–4185

Data in this issue of Diabetes by Liang et al. (p. 4064) provide insight into how the signaling that occurs between the liver and the brain during prolonged fasting helps maintain glucose homeostasis. Previous work has demonstrated that the nuclear receptor PPARα controls hepatic secretion of fibroblast growth factor 21 (FGF21) under conditions of fasting and starvation. In various studies, FGF21 has been implicated in processes as diverse as energy expenditure, insulin sensitivity, physical activity, and circadian behavior. Although this hormone can cross the blood-brain barrier and is known to be involved in gluconeogenesis, its central actions on glucose regulation during fasting have remained elusive. The newly published data provide insight on this complex question using a series of experiments with both PPARα knockout (KO) and FGF21 KO mice. The experiments demonstrated that both groups of KO mice showed similar levels of hypoglycemia in response to fasting, that this condition was due to defects in hepatic gluconeogenesis, and that the observed hypoglycemia could be reversed by central administration of FGF21. The hypoglycemia observed in the FGF21 KO mice was shown to result from impaired activation of the hypothalamic-pituitary-adrenal axis, which was accompanied by diminished corticosterone release. These findings support the idea that the PPARα-FGF21 axis plays a critical role in glucose regulation in the fasted state, and they also highlight the complex interactions between the liver and brain that are necessary to maintain euglycemia. — Helaine E. Resnick, PhD, MPH

Liang et al. FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes 2014;63:4064–4075

Although arterial calcification decreases arterial wall elasticity and contributes significantly to cardiovascular morbidity and mortality in diabetes, its pathogenesis is not well understood. In this issue of Diabetes, Cheng et al. (p. 4326) report new findings that support a functional link between the Msx genes and arteriosclerotic calcification in mice. In particular, the new data provide intriguing insights into how Msx impacts vascular myofibroblasts and smooth muscle cells. Among other developmental processes, homeobox transcription factors Msx1 and Msx2 are involved in the formation of the heart valve as well as the promotion of skeletal growth. Earlier work has demonstrated that increased Msx signaling is associated with greater aortic calcification. In the newly published experiments, LDLR knockout mice with the SM22-Cre transgene were contrasted to LDLR^-/- mice lacking this transgene. Treatment mice exhibited decreased aortic Msx expression (95% and 34% decreases in Msx1 and Msx2, respectively) compared with controls. Treated mice also displayed decreased expression of vascular Shh (Sonic hedgehog), which is involved in multipotent mesenchymal development signaling. After groups were administered a diabetogenic high-fat diet for 2 months, total aortic calcium accumulation was 31% lower in the Msx-deficient treatment group. Markers of inflammation and oxidative stress, however, were not diminished in the treatment group, suggesting that the underlying metabolic milieu remained uncorrected by reduced Msx gene expression. Using Doppler echocardiography, the investigators also assessed aortic stiffness, an important consequence of vascular calcification. Those data showed a 30% reduction in aortic stiffness among the Msx-deficient mice. However, total aortic collagen and ascending aorta wall thickness, factors that also contribute to aortic stiffness, did not differ between the groups. Although these results suggest favorable effects associated with reducing Msx expression, the authors caution that global Msx1 and Msx2 deficiency is fatal to the embryo and that the consequences of Msx1 and Msx2 deficiency in areas other than the vasculature require further investigation. Taken together, however, the new findings suggest that targeted reductions in arterial Msx signaling may provide a new therapeutic target for reduction of vascular calcification and accompanying arterial stiffness — Wendy Chou, PhD

Cheng et al. Targeted reduction of vascular Msx1 and Msx2 mitigates arteriosclerotic calcification and aortic stiffness in LDLR-deficient mice fed diabetogenic diets. Diabetes 2014;63:4326–4337