Maternal malnutrition and anaemia in India: dysregulations leading to the 'thin-fat' phenotype in newborns

Abstract

Maternal and child malnutrition and anaemia remain the leading factors for health loss in India. Low birth weight (LBW) offspring of women suffering from chronic malnutrition and anaemia often exhibit insulin resistance and infantile stunting and wasting, together with increased risk of developing cardiometabolic disorders in adulthood. The resulting self-perpetuating and highly multifactorial disease burden cannot be remedied through uniform dietary recommendations alone. To inform approaches likely to alleviate this disease burden, we implemented a systems-analytical approach that had already proven its efficacy in multiple published studies. We utilised previously published qualitative and quantitative analytical results of rural and urban field studies addressing maternal and infantile metabolic and nutritional parameters to precisely define the range of pathological phenotypes encountered and their individual biological characteristics. These characteristics were then integrated, via extensive literature searches, into metabolic and physiological mechanisms to identify the maternal and foetal metabolic dysregulations most likely to underpin the 'thin-fat' phenotype in LBW infants and its associated pathological consequences. Our analyses reveal hitherto poorly understood maternal nutrition-dependent mechanisms most likely to promote and sustain the self-perpetuating high disease burden, especially in the Indian population. This work suggests that it most probably is the metabolic consequence of 'ill-nutrition' - the recent and rapid dietary shifts to high salt, high saturated fats and high sugar but low micronutrient diets - over an adaptation to 'thrifty metabolism' which must be addressed in interventions aiming to significantly alleviate the leading risk factors for health deterioration in India.

Keywords: 5-mTHF, 5-methyltetrahydrofolate; Anaemia; BAT, brown adipocyte tissue; EAA, essential amino acids; FA, fatty acid; GSH, glutathione; Hcy, homocysteine; LBW, low birth weight; Low birth weight; Malnutrition; PE, phosphatidylethanolamine; Pathological mechanisms; Physiological programming; SAM, S-adenosyl methionine; TG, triacylglycerol; WAT, white adipocyte tissue.

Fig. 1.

Schematic representation of the interconnected transmethylation cycle/transsulphuration pathway, a critical branching point in metabolism connecting sulphur metabolism, cofactor chemistries, biological methylations and redox homoeostasis. In these interconnected pathways, methionine synthase (MS) and betaine–homocysteine S-methyltransferase (BHMT) are zinc-dependent enzymes. In parallel, methionine adenosyltransferase (MAT), N-glycine methyltransferase (GNMT), SAH hydrolase, cystathionine β-synthetase (CBS), γ-glutamylcysteine synthetase (glutamate-cysteine ligase, GCL), methylenetetrahydrofolate reductase (MTHFR) and serine hydroxymethyltransferase (SHMT) are all regulated by zinc-dependent transcription factors. Additional zinc enzymes are histone and DNA methyltransferases and adenosine deaminase^(38,39). DHFR, dihydrofolate reductase; THF, tetrahydrofolate; MTHF, methylenetetrahydrofolate; ATP, adenosine triphosphate; ADP, adenosine diphosphate; SAM, S-adenosyl methionine; SAH, S-adenosylHcy; CSE, cystathionase; GSH, glutathione; H2S, hydrogen sulphide. Figure adapted from Azzini et al. ⁽⁸⁵⁾.

Fig. 2.

Interplay between amino acid metabolism and redox homoeostasis. The synthesis and catabolism of amino acids is interwoven into redox homoeostasis. The malate–aspartate shuttle, besides transporting NADH between the cytosol and the mitochondrial matrix, also moves the amino acids glutamate and aspartate between the two compartments and is functionally connected to the TCA cycle. When aspartate is removed from this cycle to synthesise asparagine, arginine or nucleosides, this would disrupt the cycle, requiring additional carbon input. Coupling oxaloacetate (OAA) production in oxidative TCA cycle activity with glutamate production by mitochondrial glutaminase maintains flux of α-ketoglutarate into the TCA cycle while removing OAA to permit continued activity, producing reducing potential to generate ATP. In this way, two metabolites central to homoeostasis, ATP and aspartate, are synthesised in parallel. These links go further, given that aspartate, glutamate, α-ketoglutarate and malate are functionally coupled through the malate–aspartate shuttle, which is important for moving reducing potential between the matrix and the cytosol. NADH oxidation reactions and NAD+ reduction reactions, which affect the connectivity of this network, are shown in green and red, respectively. Amino acids are represented in blue, while proteins (transporters and electron carriers) are in orange. αKG, α-ketoglutarate; 1,3 BPG, 1,3-bisphosphoglycerate; 3PG, 3-phosphoglycerate; 3PP, 3-phosphopyruvate; AcCoA, acetyl CoA; Ala, alanine; Asn, asparagine; Asp, aspartate; Cit, citrate; G3P, glyceraldehyde 3-phosphate; Gln, glutamine; Glu, glutamate; Gly, glycine; Lac, lactate; Mal, malate; NAD+, nicotinamide adenine dinucleotide; NADH, reduced NAD+; OAA, oxaloacetate; P5C, pyrroline 5-carboxylate; Pro, proline; Pyr, pyruvate; Ser, serine. Figure adapted from Vettore et al.⁽⁸⁷⁾.

Fig. 3.

De novo L-carnitine biosynthesis. (A) Carnitine is synthesised from the amino acids’ lysine and methionine. Lysine provides the carbon backbone of carnitine, and the 4-N-methyl groups originate from methionine via the transmethylation pathway (see earlier). (B) In mammals, certain proteins such as calmodulin, myosin, actin, cytochrome c and histones contain N'-trimethyl-lysine (TML) residues. N-methylation of these lysine residues occurs as a post-translational event. This reaction is catalysed by specific methyltransferases, which use S-adenosyl methionine as a methyl donor. Lysosomal hydrolysis of these proteins results in the release of TML, which is the first metabolite of carnitine biosynthesis. TML is first hydroxylated on the three-position by TML dioxygenase (TMLD) to yield 3-hydroxy TML (HTML). Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). In the last step, butyrobetaine is hydroxylated on the three-position by γ-butyrobetaine dioxygenase (BBD) to yield carnitine. Figure adapted from Vaz and Wanders⁽⁹³⁾.

Fig. 4.

Intersection between pathways of choline and methionine metabolism in the transmethylation cycle and key enzymes that control methyl group transfer: methionine adenosyltransferase 1A (MAT1A), betaine–homocysteine S-methyltransferase (BHMT), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), methylenetetrahydrofolate reductase (MTHFR), microsomal TG transfer protein (MTTP), S-adenosylhomocysteine hydrolase (SAHH), glycine-N-methyltransferase (GNMT), guanidinoacetate N-methyltransferase (GAMT), phosphatidylethanolamine N-methyltransferase (PEMT), vitamin B12 (B12), dimethylglycine (DMG), glutathione (GSH), homocysteine (HCY), S-adenosyl methionine (SAM), S-adenosylhomocysteine (SAH), tetrahydrofolate (THF), phosphatidylethanolamine (PE), phosphatidylcholine (PC), very low-density lipoprotein (VLDL). Figure adapted from Chandler and White⁽¹⁰⁰⁾.

Fig. 5.

The mechanisms whereby maternal chronic malnutrition compounded by ill-nutrition leads to the ‘thin-fat’ phenotype in newborn. Maternal diet chronically low in proteins, micronutrients and carbohydrates but high in fat, compounded by deficient hygiene (left panel) leads to multiple maternal metabolic alterations resulting in high maternal anaemia, exacerbated during pregnancy, together with placental dysfunction (middle panel). Subsequently, these maternal metabolic and placental dysfunctions induce in utero foetal development alterations resulting in low birth weight children, characterised by high subcutaneous but low abdominal adipocyte deposits and already existing insulin resistance (‘thin-fat’ phenotype, right panel). Being raised in the same environment as their parents promote significant anaemia, accompanied by stunting and wasting in late childhood, repeating the same cycle as in their parents. Should these children then be exposed, during mid-to-late childhood, to a food environment primarily consisting in highly processed products low in vitamins and micronutrients but rich in salt, sugar and fat (ill-nutrition, so-called junk food), their condition stands to be worsened by the appearance of significantly increased insulin resistance and heightened susceptibility to the pathogenesis of cardiovascular (CVD) and metabolic disorders. These individuals, after reaching sexual maturity, are likely to perpetuate this deleterious cycle via their own children.