MANF regulates hypothalamic control of food intake and body weight

Su, Yang; Yang, Huiming; Chang, Ronald; Yin, Peng; Yang, Yang; Yang, Wenli; Huang, Shanshan; Gaertig, Marta A.; Li, Shengbo Eben

doi:10.1038/s41467-017-00750-x

Cited by 56 publications

(57 citation statements)

References 61 publications

(71 reference statements)

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“…On the contrary, Manf fl/fl ::Nestin Cre/1 mice are viable and have a normal lifespan without diabetes or gross defects, but adult Manf fl/fl ::Nestin Cre/1 mice have a decreased body weight when compared with littermate Manf fl/fl controls. In a recent study, Manf knock-down by siRNA from the hypothalamus resulted in hypophagia and reduced body weight (Yang et al, 2017), suggesting that Manf fl/fl :: Nestin Cre/1 mice could be smaller due to hypophagia. However, Nestin Cre/1 mice themselves have been reported with a growth defect due to reduced levels of mouse growth hormone (Galichet et al, 2010;Declercq et al, 2015).…”

Section: Discussionmentioning

confidence: 97%

MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System

Pakarinen

Danilova

Võikar

et al. 2020

eNeuro

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Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) localized protein that regulates ER homeostasis and unfolded protein response (UPR). The biology of endogenous MANF in the mammalian brain is unknown and therefore we studied the brain phenotype of MANF-deficient female and male mice at different ages focusing on the midbrain dopamine system and cortical neurons. We show that a

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Section: Discussionmentioning

confidence: 97%

MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System

Pakarinen

Danilova

Võikar

et al. 2020

eNeuro

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“…In contrast, decreased MANF expression in the hypothalamus results in hypophagia and reduced body weight. Increased MANF at the ER has been suggested to recruit and activate PIP4k2b, thus reducing AKT phosphorylation downstream of insulin receptor signaling leading to the hyperphagia (66). This result suggests that cellular MANF levels are critical for insulin-regulated AKT phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, addition of MANF to ER-stressed b-cells might reduce ER stress and lead to increased b-cell proliferation. A recent study revealed that genetically induced MANF overexpression in the hypothalamus leads to increased feeding behavior and obesity in mice caused by impaired insulin signaling and insulin resistance in the hypothalamus (66). In contrast, decreased MANF expression in the hypothalamus results in hypophagia and reduced body weight.…”

Section: Discussionmentioning

confidence: 99%

MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic β-Cell Mass in Mice

Danilova

Belevich

et al. 2018

Diabetes

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Global lack of mesencephalic astrocyte-derived neurotropic factor (MANF) leads to progressive postnatal loss of b-cell mass and insulin-dependent diabetes in mice. Similar to Manf 2/2 mice, embryonic ablation of MANF specifically from the pancreas results in diabetes. In this study, we assessed the importance of MANF for the postnatal expansion of pancreatic b-cell mass and for adult b-cell maintenance in mice. Detailed analysis of Pdx-1Cre +/2 ::Manf fl/fl mice revealed mosaic MANF expression in postnatal pancreata and a significant correlation between the number of MANF-positive b-cells and b-cell mass in individual mice. In vitro, recombinant MANF induced b-cell proliferation in islets from aged mice and protected from hyperglycemia-induced endoplasmic reticulum (ER) stress. Consequently, excision of MANF from b-cells of adult MIP-1Cre ERT ::Manf fl/fl mice resulted in reduced b-cell mass and diabetes caused largely by b-cell ER stress and apoptosis, possibly accompanied by b-cell dedifferentiation and reduced rates of b-cell proliferation. Thus, MANF expression in adult mouse b-cells is needed for their maintenance in vivo. We also revealed a mechanistic link between ER stress and inflammatory signaling pathways leading to b-cell death in the absence of MANF. Hence, MANF might be a potential target for regenerative therapy in diabetes.

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“…Factors cause excessive accumulation of unfolded or misfolded proteins in the ER, triggering ER stress (ERS) [8]. Studies in mice revealed that MANF overexpression in hypothalamus caused insulin resistance [9], while systemic overexpression of MANF markedly improved glucose and insulin tolerance [10]. In humans, circulating MANF was found to be positively correlated with insulin resistance in patients with prediabetes, but was unrelated to insulin resistance in patients with T2DM [11].…”

Section: Introductionmentioning

confidence: 99%

Decreased Circulating MANF in Women with PCOS is Elevated by Metformin Therapy and is Inversely Correlated with Insulin Resistance and Hyperandrogenism

et al. 2020

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Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel neurotrophic factor. Although recent studies have suggested that MANF appeared to be associated with insulin resistance, the results have been inconsistent. The aim of our study was to determine the serum MANF levels in women with PCOS and controls, to investigate their relationship to insulin resistance, and to evaluate circulating MANF changes with metformin intervention in PCOS women. We conducted a series of cross-sectional and interventional studies in 90 newly diagnosed patients with PCOS and 60 age- and gender-matched controls. Oral glucose tolerance test and euglycemic-hyperinsulinemic clamps were performed to assess the glucose tolerance and insulin sensitivity. Forty-three women with PCOS were randomly assigned to six months of oral metformin therapy. Serum MANF levels were significantly lower in women with PCOS than in controls. Serum MANF levels were positively correlated with M-value and negatively correlated with body mass index (BMI), body fat percentage (FAT), homeostatic model assessment of insulin resistance (HOMA-IR), and free androgen index (FAI). Multivariate stepwise regression demonstrated that serum MANF levels were independently associated with M-value and FAI. After six months of metformin treatment, there was a significant increase in serum MANF levels in PCOS women. Serum MANF levels are decreased in women with PCOS, and are reversely related to insulin resistance and hyperandrogenism. Metformin treatment elevates serum MANF levels and alleviates insulin resistance and hyperandrogenism in PCOS women.

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MANF regulates hypothalamic control of food intake and body weight

Cited by 56 publications

References 61 publications

MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System

MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System

MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic β-Cell Mass in Mice

Decreased Circulating MANF in Women with PCOS is Elevated by Metformin Therapy and is Inversely Correlated with Insulin Resistance and Hyperandrogenism

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