Short‐term tamoxifen treatment has long‐term effects on metabolism in high‐fat diet‐fed mice with involvement of Nmnat2 in POMC neurons

Abstract

Short-term tamoxifen treatment has effects on lipid and glucose metabolism in mice fed chow. However, its effects on metabolism in mice fed high-fat diet (HFD) and the underlying mechanisms are unclear. Here, we show that tamoxifen treatment for 5 days decreases fat mass for as long as 18 weeks in mice fed HFD. Tamoxifen alters mRNA levels of some genes involved in lipid metabolism in white adipose tissue and improves glucose and insulin tolerance as well as hepatic insulin signaling for 12-20 weeks. Proopiomelanocortin (POMC) neuron-specific deletion of nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) attenuates the effects of tamoxifen on glucose and insulin tolerance. These data demonstrate that short-term injection of tamoxifen has long-term effects on lipid and glucose metabolism in HFD mice with involvement of Nmnat2 in POMC neurons.

Breast cancer endocrine therapy exhausts adipocyte progenitors promoting weight gain and glucose intolerance

“…Overall, EWD treated mice gained more weight compared with E 2 -treated mice in each diet group (P < 0.001). In contrast to several published studies [19][20][21][22]32 , TAM treatment promoted rapid weight gain, but only in HFHS fed mice (P = 0.001).…”

“…Previous studies in rodents have used doses of TAM designed to activate expression of Cre-ER transgenes, ranging from 25-300 mg/kg/day administered over a few days by IP injection or oral gavage [19][20][21][22][66][67][68][69][70] , and many have been done in males. Major metabolic outcomes reported in published studies include decreased food intake 66 , rapid adipose tissue loss [19][20][21] , adipose tissue browning 21,32 , and hepatic steatosis 68,69 . With the exception of one study conducted at cold temperature 32 and one conducted on high fat fed mice 21 , most were done on chow-fed males at ambient temperature (20-24C).…”

“…Major metabolic outcomes reported in published studies include decreased food intake 66 , rapid adipose tissue loss [19][20][21] , adipose tissue browning 21,32 , and hepatic steatosis 68,69 . With the exception of one study conducted at cold temperature 32 and one conducted on high fat fed mice 21 , most were done on chow-fed males at ambient temperature (20-24C). In contrast, we performed studies on mice at thermoneutrality (~30C) and compared HFHS-to LFLS-fed females.…”

“…A number of metabolic studies employed supra-physiological doses of TAM to induce the expression of Cre-ER transgenes (reviewed in 18 ). High-dose TAM over a short period of time leads to weight loss in mice, but this is not representative of the physiological response in breast cancer survivors [19][20][21][22] . Importantly, few reports have considered the interaction with excess adiposity, which impacts over 70% of adult women 23 .…”

Glial endozepines and energy balance: Old peptides with new tricks

“…Methodological differences might explain these discrepant results. In contrast to the use of tamoxifen, which is known to cause metabolic defects per se (Liu et al, 2018) and to promote changes in chromatin arrangement (Zhou et al, 2019) that could alter the accessibility of the loxP sites to the Cre recombinase, a single i.c.v. injection of TAT‐Cre in LepR lox/lox mice not only promotes efficient gene recombination in hypothalamic tanycytes and abrogates OP‐induced pSTAT3 activation both in tanycytes and in the tuberal hypothalamus, as previously mentioned (Guillebaud et al, 2020) but also results in a severe metabolic phenotype in mice (Duquenne et al, in revision).…”