Apolipoprotein J is a hepatokine regulating muscle glucose metabolism and insulin sensitivity

Seo, Ji A; Kang, Moon Seong; Yang, Won Mo; Hwang, Won Min; Kim, Sang Soo; Hong, Soo Hyun; Heo, Jee In; Vijyakumar, Achana; Moura, Leandro Pereira de; Üner, Aykut Göktürk; Hu, Huang; Lee, Seung Hwan; Lima, Inês S.; Park, Kyong Soo; Kim, Min Seon; Dagon, Yossi; Willnow, Thomas E.; Aroda, Vanita R.; Ciaraldi, Theodore P.; Henry, Robert R.; Kim, Young–Bum

doi:10.1038/s41467-020-15963-w

Cited by 48 publications

(46 citation statements)

References 61 publications

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“…Male LRP1 loxP/loxP mice and AgRP-Cre; LRP1 loxP/loxP mice at 8 wk of age were used for GTT and ITT. The area under the curve or above the curve for glucose was calculated using the trapezoidal rule for GTT or ITT (29).…”

Section: Glucose Tolerance and Insulin Tolerance Testmentioning

confidence: 99%

LRP1 regulates food intake and energy balance in GABAergic neurons independently of leptin action

Kang

Seo

Lee

et al. 2021

American Journal of Physiology-Endocrinology and Metabolism

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Low-density lipoprotein receptor-related protein 1 (LRP1) is a member of LDL receptor family that plays a key role in systemic glucose and lipid homeostasis. LRP1 also regulates energy balance in the hypothalamus by mediating leptin’s anorexigenic action, although the underlying neurocircuitry involved is still unclear. Because GABAergic neurons are a major mediator of hypothalamic leptin action, we studied the role of GABAergic LRP1 in energy balance and leptin action using mice lacking LRP1 in Vgat- or AgRP-expressing neurons (Vgat-Cre; LRP1 loxP/loxP or AgRP-Cre; LRP1 loxP/loxP). Here, we show that LRP1 deficiency in GABAergic neurons results in severe obesity in male and female mice fed a normal-chow diet. This effect is most likely due to increased food intake and decreased energy expenditure and locomotor activity. Increased adiposity in GABAergic neuron-specific LRP1-deficient mice is accompanied by hyperleptinemia and hyperinsulinemia. Insulin resistance and glucose intolerance in these mice are occurred without change in body weight. Importantly, LRP1 in GABAergic neurons is not required for leptin action, as evidenced by normal leptin’s anorexigenic action and leptin-induced hypothalamic Stat3 phosphorylation. In contrast, LRP1 deficiency in AgRP neurons has no effect on adiposity and caloric intake. In conclusion, our data identify GABAergic neurons as a key neurocircuitry that underpins LRP1-dependent regulation of systemic energy balance and body-weight homeostasis. We further find that the GABAergic LRP1 signaling pathway modulates food intake and energy expenditure independently of leptin signaling and AgRP neurons.

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Section: Glucose Tolerance and Insulin Tolerance Testmentioning

confidence: 99%

LRP1 regulates food intake and energy balance in GABAergic neurons independently of leptin action

Kang

Seo

Lee

et al. 2021

American Journal of Physiology-Endocrinology and Metabolism

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“…Since we found that increased CLU levels in pancreas and liver from the tissue specific CLU Tg mice do not induce premature onset of diabetes but exacerbate INS intolerance, we suggest that pancreas specific CLU upregulation may result in deregulation of the GLU-INS metabolic pathway. In support, CLU was identified recently as a hepatokine that targets muscle (a tissue particularly enhanced in males) GLU metabolism and INS sensitivity through low-density lipoprotein receptor-related protein-2 along with the INS receptor signaling cascade [ 22 ]. Elevated GLU levels upregulate the metabolic genes akt , foxo1 , pgc-1 , g6pc and pepck in the liver, where activation of the phosphoinositol 3-kinase/AKT pathway inhibits the rate-controlling enzymes of gluconeogenesis and promotes glycogen synthesis [ 23 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

Clusterin overexpression in mice exacerbates diabetic phenotypes but suppresses tumor progression in a mouse melanoma model

Cheimonidi

Grivas

Sesti

et al. 2021

Aging

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Clusterin (CLU) is an ATP-independent small heat shock protein-like chaperone, which functions both intra- and extra-cellularly. Consequently, it has been functionally involved in several physiological (including aging), as well as in pathological conditions and most age-related diseases, e.g., cancer, neurodegeneration, and metabolic syndrome. To address CLU function at an in vivo model we established CLU transgenic (Tg) mice bearing ubiquitous or pancreas-targeted CLU overexpression (OE). Our downstream analyses in established Tg lines showed that ubiquitous or pancreas-targeted CLU OE in mice affected antioxidant, proteostatic and metabolic pathways. Targeted OE of CLU in the pancreas, which also resulted in CLU upregulation in the liver likely via systemic effects, increased basal glucose levels in the circulation and exacerbated diabetic phenotypes. Furthermore, by establishing a syngeneic melanoma mouse tumor model we found that ubiquitous CLU OE suppressed melanoma cells growth, indicating a likely tumor suppressor function in early phases of tumorigenesis. Our observations provide in vivo evidence corroborating the notion that CLU is a potential modulator of metabolic and/or proteostatic pathways playing an important role in diabetes and tumorigenesis.

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“…Secretory clusterin is also known as ApoJ. ApoJ has recently been identified as a novel hepatokine, and deletion of hepatic ApoJ leads to insulin resistance and glucose tolerance[28]. Furthermore, in humans, serum ApoJ levels correlate directly with increases in insulin resistance and these levels decrease in response to rosiglitazone treatment[29].…”

Section: Discussionmentioning

confidence: 99%

Areca catechu-(Betel-nut)-induced whole transcriptome changes associated with diabetes, obesity and metabolic syndrome in a human monocyte cell line

Cardosa

Ogunkolade

Lowe³

et al. 2020

Preprint

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Betel-nut consumption is the fourth most common addictive habit globally and there is good evidence to link it with obesity, type 2 diabetes and the metabolic syndrome. We adopted a genome-wide transcriptomic approach in a human monocyte cell line incubated with arecoline and its nitrosated products to identify gene expression changes relevant to obesity, type 2 diabetes and the metabolic syndrome. The THP1 monocyte cell line was incubated separately with arecoline and 3-methylnitrosaminopropionaldehyde (MNPA) in triplicate for 24 hours and pooled cDNA indexed paired-end libraries were sequenced (Illumina NextSeq 500). After incubation with arecoline and MNPA, 15 and 39 genes respectively had significant changes in their expression (q<0.05, log fold change 1.5). Eighteen of those genes have reported associations with type 2 diabetes and obesity in humans; of these genes there was strong evidence to implicate CLEC10A , MAPK8IP1 , NEGR1 , NQ01 and INHBE . In summary, these pilot studies have identified a large number of genes whose expression was changed significantly in human TPH1 cells following incubation with arecoline or with 3-methylnitrosaminopropionaldehyde. These findings suggest that further investigation of these genes in betel-quid chewers with obesity and/or type 2 diabetes is warranted.

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Apolipoprotein J is a hepatokine regulating muscle glucose metabolism and insulin sensitivity

Cited by 48 publications

References 61 publications

LRP1 regulates food intake and energy balance in GABAergic neurons independently of leptin action

LRP1 regulates food intake and energy balance in GABAergic neurons independently of leptin action

Clusterin overexpression in mice exacerbates diabetic phenotypes but suppresses tumor progression in a mouse melanoma model

Areca catechu-(Betel-nut)-induced whole transcriptome changes associated with diabetes, obesity and metabolic syndrome in a human monocyte cell line

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