With the increasing prevalence of obesity in women of reproductive age there is a need to understand the ramifications of this on offspring. The purpose of this study is to investigate the programming effects of maternal obesity during preconception and the preconception/gestational period on adiposity and adipose tissue inflammation in offspring using an animal model. Adult female C57Bl/6J mice were assigned either normal diet, high fat diet (HFD) prior to pregnancy, or HFD prior to and through pregnancy. Some offspring were maintained on normal diet while others started HFD later in life. Offspring were assessed for body composition and metabolic responses. Lipid storing tissues were evaluated for expansion and inflammation. Male offspring from the preconception group had the greatest weight gain, most subcutaneous adipose tissue, and largest liver mass when introduced to postnatal HFD. Male offspring of the preconception/gestation group had worsened glucose tolerance and an increase in resident (CD11c−) adipose tissue macrophages (ATMs) when exposed to postnatal HFD. Female offspring had no significant difference in any parameter between the diet treatment groups. In conclusion, this study demonstrates that prenatal and pregnancy windows have independent programming effects on offspring. Preconception exposure affects body composition and adiposity while gestation exposure affects metabolism and tissue immune cell phenotypes.

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Overnutrition during critical windows of development plays a significant role in life-long metabolic disease risk. Early exposure to excessive nutrition may result in altered programming leading to increased susceptibility to obesity, inflammation, and metabolic complications. This study investigated the programming effects of high-fat diet (HFD) exposure during the lactation period on offspring adiposity and inflammation. Female C57Bl/6J dams were fed a normal diet or a 60% HFD during lactation. Offspring were weaned onto a normal diet until 12 weeks of age when half were re-challenged with HFD for 12 weeks. Metabolic testing was performed throughout adulthood. At 24 weeks, adipose depots were isolated and evaluated for macrophage profiling and inflammatory gene expression. Males exposed to HFD during lactation had insulin resistance and glucose intolerance as adults. After re-introduction to HFD, males had increased weight gain and worsened insulin resistance and hyperglycemia. There was increased infiltration of pro-inflammatory CD11c+ adipose tissue macrophages, and bone marrow was primed to produce granulocytes and macrophages. Bone density was lower due to enhanced marrow adiposity. This study demonstrates that maternal HFD exposure during the lactational window programs offspring adiposity, inflammation, and impaired glucose homeostasis.

Obesity is associated with systemic inflammation and immune cell recruitment to metabolic tissues. Sex differences have been observed where male mice challenged with high fat diet (HFD) exhibit greater adipose tissue inflammation than females demonstrating a role for sex hormones in differential inflammatory responses. Circulating monocytes that respond to dietary lipids and chemokines and produce cytokines are the primary source of recruited adipose tissue macrophages (ATMs). In this study, we investigated sexual dimorphism in biological pathways in HFD-fed ATMs from male and female mice by RNA-seq. We also conducted chemotaxis assays to investigate sex differences in the migration of monocytes isolated from bone marrow from male and female mice toward a dietary saturated lipid — palmitate (PA), and a chemokine — monocyte chemoattractant protein 1 (MCP1), factors known to stimulate myeloid cells in obesity. ATM RNA-Seq demonstrated sex differences of both metabolic and inflammatory activation, including pathways for chemokine signaling and leukocyte trans-endothelial migration. In vivo monocyte transfer studies demonstrated that male monocytes traffic to female adipose tissue to generate ATMs more readily. In chemotaxis assays, lean male monocytes migrated in greater numbers than females toward PA and MCP1. With short-term HFD, male and female monocytes migrated similarly, but in chronic HFD, male monocytes showed greater migration than females upon PA and MCP1 stimulation. Studies with monocytes from toll-like receptor 4 knockout mice (Tlr4-/-) demonstrated that both males and females showed decreased migration than WT in response to PA and MCP1 implying a role for TLR4 in monocyte influx in response to meta-inflammation. Overall, these data demonstrate the role of sexual dimorphism in monocyte recruitment and response to metabolic stimuli that may influence meta-inflammation in obesity.