The hypothalamic arcuate nucleus: A key site for mediating leptin’s effects on glucose homeostasis and locomotor activity

Coppari, Roberto; Ichinose, Masumi; Lee, Charlotte E.; Pullen, Abigail E.; Kenny, Christopher D.; McGovern, Robert A.; Tang, Vinsee; Liu, Shun M.; Ludwig, Thomas; Chua, Streamson C.; Lowell, Bradford B.; Elmquist, Joel K.

doi:10.1016/j.cmet.2004.12.004

Cited by 415 publications

(380 citation statements)

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“…Traditionally, hyperglycemia and hyperinsulinemia have been considered to be secondary consequences of obesity. However, recent observations indicate that the diabetes and obesity phenotypes can be separated (29,30). Our results are consistent with those observations as silencing of OB-RGRP in the ARC prevented the development of DIO but not of hyperglycemia or hyperinsulinemia.…”

Section: Evolutionary Conservation Of the Coexpression Of Ob-r And Itsupporting

confidence: 82%

Silencing of OB-RGRP in mouse hypothalamic arcuate nucleus increases leptin receptor signaling and prevents diet-induced obesity

Couturier

Sarkis

Séron

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

106

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Obesity is a major public health problem and is often associated with type 2 diabetes mellitus, cardiovascular disease, and metabolic syndrome. Leptin is the crucial adipostatic hormone that controls food intake and body weight through the activation of specific leptin receptors (OB-R) in the hypothalamic arcuate nucleus (ARC). However, in most obese patients, high circulating levels of leptin fail to bring about weight loss. The prevention of this ''leptin resistance'' is a major goal for obesity research. We report here a successful prevention of diet-induced obesity (DIO) by silencing a negative regulator of OB-R function, the OB-R gene-related protein (OB-RGRP), whose transcript is genetically linked to the OB-R transcript. We provide in vitro evidence that OB-RGRP controls OB-R function by negatively regulating its cell surface expression. In the DIO mouse model, obesity was prevented by silencing OB-RGRP through stereotactic injection of a lentiviral vector encoding a shRNA directed against OB-RGRP in the ARC. This work demonstrates that OB-RGRP is a potential target for obesity treatment. Indeed, regulators of the receptor could be more appropriate targets than the receptor itself. This finding could serve as the basis for an approach to identifying potential new therapeutic targets for a variety of diseases, including obesity.leptin receptor overlapping transcript ͉ leptin resistance ͉ gene therapy ͉ receptor trafficking ͉ metabolic syndrome L eptin and its receptor (OB-R) were initially identified and characterized because of their involvement in the regulation of energy balance, metabolism, and neuroendocrine responses to food intake (1). Subsequently, leptin has also been shown to be important in wound healing (2), angiogenesis (3), and bone mass and immune system regulation (4, 5). OB-R belongs to the class I cytokine receptor family, which typically uses the JAK/STAT signaling pathway (6). The human OB-R gene on chromosome 1 generates multiple transcripts. Several of these transcripts encode at least five OB-R isoforms, including the short OB-Ra isoform and the long signaling-competent OB-Rb isoform (1). An additional transcript is generated from the same locus encoding a protein called OB-RGRP [or leptin receptor overlapping transcript (LEPROT)], which does not share any sequence similarity with OB-R (7). In situ hybridization experiments show coexpression of the OB-R transcript and the associated OB-RGRP transcript in the mouse brain, including hypothalamic regions involved in body weight regulation (8). Evolutionarily conserved coexpression of two ORFs is often observed in prokaryotes and viruses; however, there are few known cases in eukaryotes (9). Mammals have a single OB-RGRP homologue called LEPROTL1 (leptin receptor overlapping transcript-like 1), that has 70% amino acid sequence similarity with OB-RGRP and whose gene maps on chromosome 8 in humans (10). In yeast, Vps55p, a functional homologue of OB-RGRP, plays a role in protein transport from the Golgi to the vacuole and in the late endoc...

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Section: Evolutionary Conservation Of the Coexpression Of Ob-r And Itsupporting

confidence: 82%

Silencing of OB-RGRP in mouse hypothalamic arcuate nucleus increases leptin receptor signaling and prevents diet-induced obesity

Couturier

Sarkis

Séron

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

106

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“…By chiefly acting on neurons within the CNS, leptin suppresses food intake and increases energy expenditure, and hence restrains excessive body weight gain (16). In addition, leptin directly governs glucose homeostasis, mainly by activating cognate leptin receptors (LEPRs) in neurons within the hypothalamic arcuate nucleus (ARH) (17)(18)(19)(20). Interestingly, leptin and insulin share similar intracellular signaling pathways in hypothalamic neurons, such as the PI3K signaling cascade (21,22).…”

mentioning

confidence: 99%

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Fujikawa

Chuang

Sakata

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

182

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Leptin monotherapy reverses the deadly consequences and improves several of the metabolic imbalances caused by insulindeficient type 1 diabetes (T1D) in rodents. However, the mechanism(s) underlying these effects is totally unknown. Here, we report that intracerebroventricular (icv) infusion of leptin reverses lethality and greatly improves hyperglycemia, hyperglucagonemia, hyperketonemia, and polyuria caused by insulin deficiency in mice. Notably, icv leptin administration leads to increased body weight while suppressing food intake, thus correcting the catabolic consequences of T1D. Also, icv leptin delivery improves expression of the metabolically relevant hypothalamic neuropeptides proopiomelanocortin, neuropeptide Y, and agouti-related peptide in T1D mice. Furthermore, this treatment normalizes phosphoenolpyruvate carboxykinase 1 contents without affecting glycogen levels in the liver. Pancreatic β-cell regeneration does not underlie these beneficial effects of leptin, because circulating insulin levels were undetectable at basal levels and following a glucose overload. Also, pancreatic preproinsulin mRNA was completely absent in these icv leptin-treated T1D mice. Furthermore, the antidiabetic effects of icv leptin administration rapidly vanished (i.e., within 48 h) after leptin treatment was interrupted. Collectively, these results unveil a key role for the brain in mediating the antidiabetic actions of leptin in the context of T1D.brain | leptin monotherapy | glucose homeostasis | glucagon suppression A ccording to the Juvenile Diabetes Research Foundation, type 1 diabetes (T1D) afflicts 1-3 million people in the United States alone. Regrettably, for reasons yet to be understood, the incidence of T1D has been increasing at an alarming annual rate of ∼3%, thus indicating that the number of patients with T1D is predicted to rise significantly in the future (1). T1D occurs as a consequence of pancreatic β-cell destruction leading to insulin deficiency, a defect that causes hyperglycemia, hyperglucagonemia, cachexia, ketoacidosis, and other abnormalities (2, 3). T1D is a deadly condition if not treated. Current life-saving interventions include daily insulin administration; insulin therapy reduces hyperglycemia, glycosylated hemoglobin, and cachexia and prevents or delays some T1D-associated morbidities (3, 4). However, even with insulin therapy, T1D secondary complications include debilitating and long-lasting conditions, such as heart disease, neuropathy, and hypertension (5-7). Moreover, probably because of insulin's lipogenic and cholesterologenic actions, longterm insulin treatment is suspected to underlie the increased ectopic lipid deposition (i.e., in nonadipose tissues) (8) and incidence of coronary artery disease (>90% after the age of 55 y) (9, 10) seen in patients with T1D. Furthermore, in part attributable to insulin's potent, fast-acting, glycemia-lowering effects, intensive insulin therapy significantly increases the risk for hypoglycemia, an event that is disabling and can even be fatal (3,(11...

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“…There is a direct relationship between blood glucose concentration and food ingestion. The hypothalamus has leptin receptors that participate in the regulation of glucose homeostasis (Coppari et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Seminal Parameters and Sexual Behavior on Farm Rabbits Provided with a Diet Supplemented with Canola Oil at the Start of Puberty

2018

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MEJÍA, H. N. G.; HERNÁNDEZ, E. J. & PÉREZ-MARTÍNEZ, M.Seminal parameters and sexual behavior on farm rabbits provided with a diet supplemented with canola oil at the start of puberty. Int. J. Morphol., 36(1):59-62, 2018. SUMMARY:In order to evaluate the effect on sexual behavior and spermatic parameters of white New Zealand rabbits, at the onset of puberty, they were fed a standard diet supplemented with canola oil (obesogenic). Two groups were formed; one of which received daily 180 g of a standard commercial diet supplemented with 13 ml of canola oil during 12 weeks, while the second group (control) were fed daily 180 g of only the standard commercial diet. Starting at 20-weeks of age, seminal volume, en masse and individual sperm motility, and sperm concentration per mm 3 were measured from each individual, as well as the behaviors olfactory exploration, chinning, and first and second attempt at mounting were assessed. No significant differences were found between groups in terms of seminal volume, and en masse and individual sperm motility count and percentage (P>0.05). In relation to sexual behavior, the group fed with supplemental canola oil showed reduced the response time to females in the sexual behaviors of chinning, olfactory exploration, and first and second attempt at mounting when compared to the control group (P<0.01). The data indicate that the addition of canola oil to a standard rabbit diet at the start of puberty and continued for 12 weeks increases the body mass index and reduces the response time in sexual behaviors such as olfactory exploration, chinning, and second attempt at mounting when interacting with female stimulus. Nevertheless, the seminal parameters did not show any modification. Other studies are needed to show the benefits or disadvantages of the addition of varying inclusion percentages of other vegetable oils, to evaluate their effects on reproductive efficiency in breeder male rabbits.

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The hypothalamic arcuate nucleus: A key site for mediating leptin’s effects on glucose homeostasis and locomotor activity

Cited by 415 publications

References 53 publications

Silencing of OB-RGRP in mouse hypothalamic arcuate nucleus increases leptin receptor signaling and prevents diet-induced obesity

Silencing of OB-RGRP in mouse hypothalamic arcuate nucleus increases leptin receptor signaling and prevents diet-induced obesity

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Seminal Parameters and Sexual Behavior on Farm Rabbits Provided with a Diet Supplemented with Canola Oil at the Start of Puberty

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