Injury to hypothalamic Sim1 neurons is a common feature of obesity by exposure to high‐fat diet in male and female mice

Abstract

The hypothalamus is essential for regulation of energy homeostasis and metabolism. Feeding hypercaloric, high‐fat (HF) diet induces hypothalamic arcuate nucleus injury and alters metabolism more severely in male than in female mice. The site(s) and extent of hypothalamic injury in male and female mice are not completely understood. In the paraventricular nucleus (PVN) of the hypothalamus, single‐minded family basic helix‐loop helix transcription factor 1 (Sim1) neurons are essential to control energy homeostasis. We tested the hypothesis that exposure to HF diet induces injury to Sim1 neurons in the PVN of male and female mice. Mice expressing membrane‐bound enhanced green fluorescent protein (mEGFP) in Sim1 neurons (Sim1‐Cre:Rosa‐mEGFP mice) were generated to visualize the effects of exposure to HF diet on these neurons. Male and female Sim1‐Cre:Rosa‐mEGFP mice exposed to HF diet had increased weight, hyperleptinemia, and developed hepatosteatosis. In male and female mice exposed to HF diet, expression of mEGFP was reduced by > 40% in Sim1 neurons of the PVN, an effect paralleled by cell apoptosis and neuronal loss, but not by microgliosis. In the arcuate nucleus of the Sim1‐Cre:Rosa‐mEGFP male mice, there was decreased alpha‐melanocyte‐stimulating hormone in proopiomelanocortin neurons projecting to the PVN, with increased cell apoptosis, neuronal loss, and microgliosis. These defects were undetectable in the arcuate nucleus of female mice exposed to the HF diet. Thus, injury to Sim1 neurons of the PVN is a shared feature of exposure to HF diet in mice of both sexes, while injury to proopiomelanocortin neurons in arcuate nucleus is specific to male mice. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Delivery of phosphatidylethanolamine blunts stress in hepatoma cells exposed to elevated palmitate by targeting the endoplasmic reticulum

“…We have found that exposure of mice to lard-based HF diet induces loss of liver PE, which takes place even before the onset of obesity 13 . Here, we find that loss of PE takes place also in the liver of obese mice exposed to a palm oilbased HF diet and is concomitant to hepatosteatosis.…”

“…In mice exposed to a palm oil-based HF diet, onset of hepatosteatosis is paralleled by loss of Grp78/Bip in pericentral hepatocytes A HF diet with 45% Kcal fat from lard has been used to study effects of lipid stress in rodents [14][15][16] . We have here modified this diet by substituting lard with palm oil 13 , which reflect more closely the lipid composition of human diets [17][18][19] . Mice were treated with LF and palm oil-based HF diet for a total of 14 weeks.…”

“…We have recently found that exposure to the lard-based HF diet induces loss of PE but not of PC, in liver 13 . Here, we asked whether exposure to palm oil-based HF diet altered liver PC and PE abundance and composition.…”

“…As PE is reduced in the liver of mice fed lard and palm oil-based HF diets ( Fig. 2 and data by Nyamugenda et al 13 ), we asked whether delivery of PE to Hepa1-6 cells treated with the elevated palmitate would change response to lipid stress. When PE was added together with the elevated palmitate to the Hepa1-6 cell medium, Grp78/BiP and XBP1s mRNA abundance was increased as compared to cells kept under control conditions, indicating that the transcriptional execution of the UPR induced by elevated fatty acid is still taking place ( Fig.…”

“…Mitofusin 2 deficiency in mice also alters phospholipid composition, by inducing defective transfer of phosphatidylserine from ER to mitochondria to synthesize PE and liver disease 12 . Exposure to a lard-based HF diet induces changes of liver phospholipid composition including lowering PE abundance 13 . Here, we asked whether obesity by exposure to palm oil based HF diet has also effects to decrease liver PE abundance and to promote ER stress.…”