Short-term post-weaning nutrition can result in long-lasting effects in later life. Partial replacement of glucose by galactose in the post-weaning diet showed direct effects on liver inflammation. Here, we examined this program on body weight, body composition, and insulin sensitivity at the adult age. Three-week-old female C57BL/6JRccHsd mice were fed a diet with glucose plus galactose (GAL; 16 energy% (en%) each) or a control diet with glucose (GLU; 32 en%) for three weeks, and afterward, both groups were given the same high-fat diet (HFD). After five weeks on a HFD, an oral glucose tolerance test was performed. After nine weeks on a HFD, energy metabolism was assessed by indirect calorimetry, and fasted mice were sacrificed fifteen minutes after a glucose bolus, followed by serum and tissue analyses. Body weight and body composition were not different between the post-weaning dietary groups, during the post-weaning period, or the HFD period. Glucose tolerance and energy metabolism in adulthood were not affected by the post-weaning diet. Serum adiponectin concentrations were significantly higher (p = 0.02) in GAL mice while insulin, leptin, and insulin-like growth factor 1 concentrations were not affected. Expression of Adipoq mRNA was significantly higher in gonadal white adipose tissue (gWAT; p = 0.03), while its receptors in the liver and skeletal muscles remained unaffected. Irs2 expression was significantly lower in skeletal muscles (p = 0.01), but not in gWAT or Irs1 expression (in both tissues). Gene expressions of inflammatory markers in gWAT and the liver were also not affected. Conclusively, galactose in the post-weaning diet significantly improved circulating adiponectin concentrations and reduced skeletal muscle Irs2 expression in adulthood without alterations in fat mass, glucose tolerance, and inflammation.

Early‐life nutrition can exert long‐lasting effects on later‐life health. Given that lactose is extensively consumed during early mammalian development, this raises the intriguing possibility that lactose or its constituent galactose may exert beneficial nutritional programming effects. We tested here whether early‐life (larval period) co‐consumption of galactose and glucose (GALGLU; as in hydrolysed lactose) shapes later‐life (adult) lifespan in Drosophila melanogaster . Larval GALGLU versus isocaloric glucose consumption (GLU) significantly extended the developmental time of larvae, increased the pupal volume, decreased pupal oxygen consumption, and reduced the pupal mitochondrial mass. These early‐life effects were translated into sexually dimorphic effects on adult lifespan. Specifically, larval GALGLU consumption extended the lifespan of females when challenged with an obesogenic adult diet, whereas it reduced lifespan in males. To identify molecular correlates of the female‐specific benefit, we profiled transcriptomes and lipidomes. Notably, larval GALGLU induced later‐life transcriptional activation of cuticular hydrocarbon (CHC)‐synthesizing enzymes, including the diene‐producing desaturase Fad2 , without changes in the monounsaturated fatty acid (MUFA)‐producing desaturase Desat1 , indicating increased MUFA demand without increased supply. Lipidomic analysis revealed decreased MUFA‐containing and increased polyunsaturated fatty acid (PUFA)‐containing glycerophospholipids. These data suggest that enhanced CHC biosynthesis depletes cellular MUFAs, driving compensatory incorporation of PUFAs into glycerophospholipids. Concluding, early‐life galactose and glucose co‐consumption programs sexually dimorphic lifespan, specifically by counteracting the lifespan‐shortening effects of obesogenic diets in adult females, and redirects adult female lipid metabolism toward a PUFA‐enriched glycerophospholipid profile.

Galactose, a component of lactose, has nutritional programming power in mice. Lactose‐free formulae contain maltodextrin, but no galactose. Here, partly replacing maltodextrin with galactose in the post‐weaning diet was investigated for its metabolic and nutritional programming effects. Female and male mice were fed 39 energy% (en%) maltodextrin and 8 en% glucose (CON), or 31 en% maltodextrin with 16 en% galactose (GAL), or 15 en% maltodextrin and 16 en% galactose plus 16 en% glucose (lactose‐mimic, LM) from postnatal week (PW) 3 to PW6. Body weight, fat mass, lean mass, energy expenditure (EE), and respiratory exchange ratio (RER) were lower at PW6 in female GAL and LM mice ( p < 0.05). After receiving 9 weeks of the same obesogenic high‐fat diet, the expression of hepatic insulin‐like growth factor 1 ( Igf1 ) appeared lower in both galactose‐fed groups in females ( p < 0.05). Partly replacing maltodextrin with galactose or galactose plus glucose in a post‐weaning diet in mice resulted in significantly lower body weight, fat and lean mass, EE, and RER in early‐life, and had no obvious nutritional programming effects except on liver Igf1 mRNA in females in later‐life. The implications of this programming effect remain to be investigated further.

Early-life nutrition can exert long-lasting effects on later-life health. Given that lactose is extensively consumed during early mammalian development, this raises the intriguing possibility that lactose or its constituent galactose may exert beneficial nutritional programming effects. We tested here whether early-life (larval period) co-consumption of galactose and glucose (GALGLU; as in hydrolysed lactose) shapes later-life (adult) lifespan in Drosophila melanogaster. Larval GALGLU versus isocaloric glucose consumption (GLU) significantly extended the developmental time of larvae, increased the pupal volume, decreased pupal oxygen consumption, and reduced the pupal mitochondrial mass. These early-life effects were translated into sexually dimorphic effects on adult lifespan. Specifically, larval GALGLU consumption extended the lifespan of females when challenged with an obesogenic adult diet, whereas it reduced lifespan in males. To identify molecular correlates of the female-specific benefit, we profiled transcriptomes and lipidomes. Notably, larval GALGLU induced later-life transcriptional activation of cuticular hydrocarbon (CHC)-synthesizing enzymes, including the diene-producing desaturase Fad2, without changes in the monounsaturated fatty acid (MUFA)-producing desaturase Desat1, indicating increased MUFA demand without increased supply. Lipidomic analysis revealed decreased MUFA-containing and increased polyunsaturated fatty acid (PUFA)-containing glycerophospholipids. These data suggest that enhanced CHC biosynthesis depletes cellular MUFAs, driving compensatory incorporation of PUFAs into glycerophospholipids. Concluding, early-life galactose and glucose co-consumption programs sexually dimorphic lifespan, specifically by counteracting the lifespan-shortening effects of obesogenic diets in adult females, and redirects adult female lipid metabolism toward a PUFA-enriched glycerophospholipid profile.

Background: Lactose, a disaccharide of glucose and galactose, is the primary carbohydrate found in milk. Recently, there has been an increased demand for low lactose/lactose-free infant formulas. Maltodextrin (MDX) is a popular, alternative carbohydrate source in these formulas, yet the (long-term) health effects of consuming maltodextrin in early life are unclear. Previously, consuming galactose (partly replacing glucose) in a postweaning diet was shown to improve metabolic health in mice. Objective: To investigate the effects of partly replacing MDX with galactose in post-weaning diets on body composition and energy metabolism. Methods: Weaned, individually housed female C57BL/6JRccHsd mice received isocaloric diets (in a dough ball format) with different carbohydrate profiles for three weeks (postnatal day (PN)21-PN42). GLUGAL (lactose mimic, n = 13) contained 15.7 en% glucose, 15.7 en% galactose and 14.9 en% MDX, and GAL (n = 12) contained 15.7 en% galactose, no glucose and 30.6 en% MDX. MDX (n = 13) contained 38.4 en% MDX and 7.9 en% glucose. Energy metabolism was assessed via indirect calorimetry from PN40-PN42. At PN42, all mice were challenged with a 40 en% high-fat diet (HFD) until PN105. Body composition was measured weekly using Echo-MRI. At PN105, fasted (4 h) mice were sacrificed for serum and tissue analysis. Results: At PN42, mice in both galactose-fed groups (GLUGAL and GAL) had a significantly lower body weight, fat mass and relative fat mass compared with the MDX group (p < 0.0001). The respiratory exchange ratio was significantly lower in both galactose-fed groups compared with the MDX group (p < 0.05), suggesting lower carbohydrate oxidation and thus higher relative fat oxidation levels. In parallel, both galactose-fed groups showed lower energy expenditure (p < 0.05). Discussion: The GAL mice were similar to the GLUGAL (lactose mimic) mice in terms of body weight, composition and energy metabolism, while being significantly different from the MDX group at PN42. These findings suggest an improvement of body composition and energy metabolism when replacing MDX with galactose. This study is the first to compare the effects of replacing part of MDX with galactose in early life and reinforces the impact of the type of carbohydrates on metabolic outcomes.